U.S. patent application number 10/479262 was filed with the patent office on 2005-01-27 for modulators of peroxisome proliferator activated receptors.
Invention is credited to Alfredo Martin, Jose, Ardecky, Robert J, Brooks, Dawn Alisa, Crespo, Rafael Ferritto, Gonzales Garcia, Maria Rosario, Lamas-Peteira, Carlos, Martin-Ortega Finger, Maria, Miller, Anne-Reifel, Montrose-Rafezadeh, Chahrzad, Prieto, Lourdes, Rojo, Isabel, Torrado, Alicia, Warshawsky, Alan M.
Application Number | 20050020684 10/479262 |
Document ID | / |
Family ID | 23145037 |
Filed Date | 2005-01-27 |
United States Patent
Application |
20050020684 |
Kind Code |
A1 |
Brooks, Dawn Alisa ; et
al. |
January 27, 2005 |
Modulators of peroxisome proliferator activated receptors
Abstract
Disclosed is a compound represented by Structural Formula (I):
Ar is a substituted or unsubstituted aromatic group. Q is a
covalent bond, --CH.sub.2-- or --CH.sub.2CH.sub.2--; W is a
substituted or unsubstituted alkylene or a substituted or
unsubstituted heteroalkylene linking group from two to ten atoms in
length, preferably from two to seven atoms in length. Phenyl Ring A
is optionally substituted with up to four substituents in addition
to R.sub.1 and W, R.sub.2 is
(CH.sub.2).sub.n--CH(OR.sub.2)--(CH.sub.2).sub.nE,
--(CH).dbd.C(OR.sub.2)--(CH.sub.2).sub.nE,
--(CH.sub.2).sub.n--CH(Y)--(CH- .sub.2).sub.mE or
(CH).dbd.C(Y)(CH.sub.2).sub.mE; wherein E is COOR.sub.3, C1-C3
alkylnitrile, carboxamide, sulfonamide, acylsulfonamide or
tetrazole and wherein sulfonamide, acylsulfonamide and tetrazole
are optionally substituted with one or more substituents
independently selected from: C1-C6 alkyl, haloalkyl and
aryl-C.sub.o-4-alkyl; R.sub.2 is H, an aliphatic group, a
substituted aliphatic group, haloalkyl, an aromatic group, a
substituted aromatic group, --COR.sub.4, --COOR.sub.4,
--CONR.sub.5R.sub.6, --C(S)R.sub.4, --C(S)OR.sub.4 or
C(S)NR.sub.5R.sub.6, R.sub.3 is H, an aliphatic group, a
substituted aliphatic group, an aromatic group or a substituted
aromatic group. Y is O--, CH.sub.2--, CH.sub.2CH.sub.2-- or
CH.dbd.CH-- and is bonded to a carbon atom in Phenyl Ring A that is
ortho to R.sub.1. R.sub.4-R.sub.6 are independently H, an aliphatic
group, a substituted aliphatic group, an aromatic group or a
substituted aromatic group. n and m are independently 0, 1 or 2.
1
Inventors: |
Brooks, Dawn Alisa;
(Indianapolis, IN) ; Warshawsky, Alan M; (Carmel,
IN) ; Montrose-Rafezadeh, Chahrzad; (Indianapolis,
IN) ; Miller, Anne-Reifel; (Indianapolis, IN)
; Prieto, Lourdes; (Madrid, ES) ; Rojo,
Isabel; (Madrid, ES) ; Alfredo Martin, Jose;
(Madrid, ES) ; Gonzales Garcia, Maria Rosario;
(Madrid, ES) ; Torrado, Alicia; (Madrid, ES)
; Crespo, Rafael Ferritto; (Madrid, ES) ;
Lamas-Peteira, Carlos; (Madrid, ES) ; Ardecky, Robert
J; (Encinitas, CA) ; Martin-Ortega Finger, Maria;
(Madrid, ES) |
Correspondence
Address: |
Steven G. Davis
Hamilton Brook Smith & Reynolds
530 Virginia Road
PO Box 9133
Concord
MA
01742-9133
US
|
Family ID: |
23145037 |
Appl. No.: |
10/479262 |
Filed: |
December 1, 2003 |
PCT Filed: |
May 30, 2002 |
PCT NO: |
PCT/US02/16950 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
60297144 |
Jun 7, 2001 |
|
|
|
Current U.S.
Class: |
514/562 ;
514/563; 562/450 |
Current CPC
Class: |
C07D 333/76 20130101;
C07D 317/22 20130101; C07D 213/30 20130101; A61P 3/04 20180101;
C07C 217/84 20130101; C07D 317/64 20130101; C07D 307/83 20130101;
C07D 295/096 20130101; C07C 2601/08 20170501; C07D 335/02 20130101;
A61P 15/00 20180101; C07C 59/68 20130101; C07C 219/10 20130101;
C07C 217/92 20130101; C07D 209/08 20130101; C07C 233/75 20130101;
C07D 231/12 20130101; C07D 249/08 20130101; C07D 277/64 20130101;
C07D 233/56 20130101; C07D 307/91 20130101; C07D 307/93 20130101;
C07C 59/90 20130101; C07D 317/20 20130101; C07D 209/48 20130101;
C07D 295/185 20130101; A61P 9/02 20180101; C07D 317/54 20130101;
A61P 1/14 20180101; A61P 9/00 20180101; C07C 217/20 20130101; C07C
233/29 20130101; C07C 235/64 20130101; A61P 3/06 20180101; C07C
235/56 20130101; C07D 215/14 20130101; A61P 9/12 20180101; C07D
217/02 20130101; C07C 239/12 20130101; C07C 255/54 20130101; C07D
311/30 20130101; A61P 3/10 20180101; C07D 333/16 20130101; C07C
233/60 20130101; C07D 295/112 20130101; C07D 257/04 20130101; C07C
233/25 20130101; A61P 9/04 20180101; C07C 59/72 20130101; C07D
307/79 20130101; A61P 3/00 20180101 |
Class at
Publication: |
514/562 ;
514/563; 562/450 |
International
Class: |
A61K 031/195; C07C
233/87 |
Claims
1. A compound represented by the following structural formula:
691or pharmaceutically acceptable salts, hydrates, stereoisomers
and solvates thereof, wherein: Ar is a substituted or unsubstituted
aromatic group; Q is a covalent bond, --CH.sub.2--,
--CH.sub.2CH.sub.2--, --CH.sub.2CH.sub.2CH.sub.2-- or
--CH.sub.2CH.sub.2CH.sub.2CH.sub.2--; W is a substituted or
unsubstituted alkylene group two to ten atoms in length or a
substituted or unsubstituted heteroalkylene group, wherein the
heteroalkylene group is an alkylene group from two to ten atoms in
length in which one or more methylene groups have been replaced
with a functional group selected from --CH.dbd.CH--, --C.ident.C--,
--O--CO--, --NR.sub.7--, --NR.sub.7CO--, --C(.dbd.NOH)--, --S--,
--S(O)--, --S(O).sub.2-- or --CH(NR.sub.7R.sub.8)--, wherein when
Ar is trifluoromethylphenyl (CF.sub.3C.sub.6H.sub.4), W is not a
C.sub.2-C.sub.3 alkylene group; phenyl Ring A is optionally
substituted with up to four substituents in addition to R.sub.1;
R.sub.1 is --(CH.sub.2).sub.n--CH(OR.sub.2)--(CH.sub.2).sub.mE,
--(CH).dbd.C(OR.sub.2)--(CH.sub.2).sub.mE,
--(CH.sub.2).sub.n--CH(Y)--(CH- .sub.2).sub.mE or
--(CH).dbd.C(Y)--(CH.sub.2).sub.mE; wherein E is COOR.sub.3,
C.sub.1-C.sub.3-alkylnitrile, carboxamide, sulfonamide,
acylsulfonamide or tetrazole and wherein sulfonamide,
acylsulfonamide and tetrazole are optionally substituted with one
or more substituents independently selected from: C1-C6 alkyl,
C1-C6 haloalkyl and aryl-C0-4-alkyl; R.sub.2 is --H, an aliphatic
group, a substituted aliphatic group, haloalkyl, an aralkyl group,
a substituted aralkyl group, an aromatic group, a substituted
aromatic group, --COR.sub.4, --COOR.sub.4, --CONR.sub.5R.sub.6,
--C(S)R.sub.4, --C(S)OR.sub.4 or --C(S)NR.sub.5R.sub.6; Y is --O--,
--CH.sub.2--, --CH.sub.2CH.sub.2-- or a --CH.dbd.CH-- group which
is bonded to a carbon atom in Phenyl Ring A that is ortho to
R.sub.1; R.sub.3-R.sub.8 are independently --H, an aliphatic group,
a substituted aliphatic group, an aromatic group or a substituted
aromatic group; and n and m are independently 0, 1 or 2.
2. A compound represented by the following structural formula:
692or pharmaceutically acceptable salts, hydrates and solvates
thereof, wherein: Ar is a substituted or unsubstituted aromatic
group; W is a substituted or unsubstituted alkylene linking group
or a substituted or unsubstituted heteroalkylene linking group from
two to ten atoms in length, wherein when Ar is
trifluoromethylphenyl (CF.sub.3C.sub.6H.sub.4)- , W is not a
C.sub.2-C.sub.3 alkylene group; phenyl Ring A is optionally
substituted with up to four substituents in addition to R.sub.1;
R.sub.1 is
--(CH.sub.2).sub.n--CH(OR.sub.2)--(CH.sub.2).sub.mCOOR.sub.3,
--(CH).dbd.C(OR.sub.2)--(CH.sub.2).sub.mCOOR.sub.3,
--(CH.sub.2).sub.n--CH(Y)--(CH.sub.2).sub.mCOOR.sub.3 or
--(CH).dbd.C(Y)--(CH.sub.2).sub.mCOOR.sub.3; R.sub.2 is --H, an
aliphatic group, a substituted aliphatic group, an aryl group, a
substituted aryl group, --COR.sub.4, --COOR.sub.4,
--CONR.sub.5R.sub.6, --C(S)R.sub.4, --C(S)OR.sub.4 or
--C(S)NR.sub.5R.sub.6; Y is --O--, --CH.sub.2--,
--CH.sub.2CH.sub.2-- or a --CH.dbd.CH-- group which is bonded to a
carbon atom in Phenyl Ring A that is ortho to R.sub.1;
R.sub.3-R.sub.6 are independently --H, an aliphatic group, a
substituted aliphatic group, an aryl group or a substituted aryl
group; and n and m are independently 0, 1 or 2.
3. The compound of claim 2 wherein Ar is represented by a
structural formula selected from: 693694695wherein: Rings B-Z are
independently substituted or unsubstituted; X is --O--, --S--,
--CH.sub.2-- or --C(O)--; Z is a covalent bond, --O--,
(--CH.sub.2).sub.q--, --CH(CH.sub.3)(CH.sub.2).sub.q--,
--C(CH.sub.3).sub.2(CH.sub.2).sub.q--,
--(CH.sub.2).sub.qCH(CH.sub.3)--,
--(CH.sub.2).sub.qC(CH.sub.3).sub.2--, --O(CH.sub.2).sub.q--,
--(CH.sub.2).sub.qO--, --(CH.sub.2).sub.qNH--,
--(CH.sub.2).sub.qNH--, --(CH.sub.2).sub.qCHR.sub.20--,
--CHR.sub.20(CH.sub.2).sub.q--,
--(CH.sub.2).sub.qCR.sub.20R.sub.20--,
--(CH.sub.2).sub.qCR.sub.20R.sub.20--,
--(CH.sub.2).sub.qNR.sub.20--, --NR.sub.20(CH.sub.2).sub.q--,
--(CH.sub.2).sub.qC(.dbd.NOH)--, --C(.dbd.NOH)(CH.sub.2).sub.q--,
--CH(OH)--(CH.sub.2).sub.q--, --(CH.sub.2).sub.q--CH(OH)--,
--CO--(CH.sub.2).sub.q--, --(CH.sub.2).sub.q--CO--,
--COO--(CH.sub.2).sub.q--, --OCO--(CH.sub.2).sub.q--,
--(CH.sub.2).sub.q--OCO--, --(CH.sub.2).sub.q--COO--,
--(CH.sub.2).sub.qCO--NH--, --(CH.sub.2).sub.qNH--CO--,
--(CH.sub.2).sub.qCONR.sub.20--, --CONR.sub.20(CH.sub.2).sub.q--,
--(CH.sub.2).sub.qNR.sub.2OCO-- or --NR.sub.20CO(CH.sub.2).sub.q--;
q is 0, 1, 2 or 3; and each R.sub.20 is independently a C1-C5 alkyl
group or a halogenated C1-C5 alkyl group.
4. The compound of claim 3 wherein the compound is represented by
the following structural formula: 696wherein: p is an integer from
one to nine W.sub.1 is --O--, --C(O)--, --OCH.sub.2--,
--CH.sub.2--, --NR.sub.8--, --NR.sub.8CO--, --NR.sub.8CH--,
--C(.dbd.NOH)-- or --CH(NR.sub.7R.sub.8)--; and R.sub.7 and R.sub.8
are independently --H, an aliphatic group, a substituted aliphatic
group, an aromatic group or a substituted aromatic group.
5. The compound of claim 3 wherein the compound is represented by
the following structural formula: 697wherein: p is an integer from
one to four; W.sub.1 is --O--, --C(O)--, --OCH.sub.2--,
--CH.sub.2--, --NR.sub.8--, --NR.sub.8CO--, --NR.sub.8CH--,
--C(.dbd.NOH)-- or --CH(NR.sub.7R.sub.8)--; and R.sub.7 and R.sub.8
are independently --H, an aliphatic group, a substituted aliphatic
group, an aromatic group or a substituted aromatic group.
6. The compound of claim 5 wherein R.sub.1 is para to W.sub.1 and
is represented by the following structural formula: 698
7. The compound of claim 5 wherein R.sub.1 is meta to W.sub.1 and
is represented by the following structural formula: 699
8. The compound of claim 6 wherein the compound is represented by a
structural formula selected from: 700701
9. The compound of claim 4 wherein the compound is represented by a
structural formula selected from: 702
10. The compound of claim 8 wherein R.sub.2 is a C1-C6 alkyl group,
phenyl, benzyl or benzoyl; and R.sub.3 is --H or a C1-C6 alkyl
group.
11. The compound of claim 10 wherein the compound is represented by
the following structural formula: 703wherein: Phenyl Rings A' and
A" independently substituted or unsubstituted and Z is --O-- or
--CO-- and p is 3 or 4.
12. The compound of claim 11 wherein Phenyl Rings A' and A" are
independently substituted with one or more groups selected from
halogen, --R.sub.9, --OR.sub.9, --COR.sub.9, --COOR.sub.9, --CN, a
non-aromatic heterocyclic group, an alkyl group,
--(CH.sub.2).sub.aCH(OR.sub.30)(CH.su- b.2).sub.bCOOR.sub.31, or
--NR.sub.9C(O)R.sub.9, R.sub.9 is --H, a C1-C.sub.10 alkyl group, a
C1-C10 halogenated alkyl group, a cycloalkyl group or an aromatic
group, R.sub.30 is a C1-C6 alkyl group or a halogenated C1-C6 alkyl
group, R.sub.31 is --H, a C1-C6 alkyl group or a halogenated C1-C6
alkyl group, and a and b are independently 0, 1 or 2.
13. The compound of claim 12 wherein Phenyl Rings A' and A" are
independently substituted with one or more groups selected from
halogen, C1-C8 straight chained or branched alkyl, C3-C8
cycloalkyl, C1-C8 straight chained or branched alkanoyl, C1-C8
straight chained or branched alkoxy, --Br, --F, N-morpholino, --CN,
--COOH, --OH, --CF.sub.3 or --OCF.sub.3.
14. The compound of claim 13 wherein Phenyl Ring A is substituted
with one or more groups selected from halogen, --OR.sub.10,
--R.sub.10, aromatic group, substituted aromatic group, aralkyl,
substituted aralkyl, aralkenyl, substituted aralkenyl, alkyl or
substituted alkyl and R.sub.10 is a C1-C.sub.10 alkyl group or a
C1-C10 halogenated alkyl group.
15. The compound of claim 14 wherein Phenyl Ring A is substituted
with one or more groups selected from --F, --Cl, --OCH.sub.3,
--OCF.sub.3, --CH.sub.3, ethyl, n-propyl, iso-propyl, alkyl,
2-phenylethenyl, 2-phenylethyl, phenyl, -o-biphenyl, -m-biphenyl,
-p-biphenyl, -o-C.sub.6H.sub.40CH.sub.3,
-m-C.sub.6H.sub.40CH.sub.3, -p-C.sub.6H.sub.40CH.sub.3,
-o-C.sub.6H.sub.4F, -m-C.sub.6H.sub.4F or -p-C.sub.6H.sub.4F.
16. The compound of claim 11 wherein R.sub.2 is methyl and R.sub.3
is hydrogen.
17. A compound represented by the following structural formula:
704or pharmaceutically acceptable salts, hydrates, stereoisomers
and solvates thereof, wherein Z is --O-- or --CO--.
18. A compound represented by the following structural formula
705or pharmaceutically acceptable salts, hydrates and solvates
thereof.
19. The compound of claim 2, wherein the compound is represented by
the following structural formula: 706wherein t is an integer from 1
to about 5.
20. The compound of claim 19 wherein the compound is represented by
the following structural formula: 707
21. The compound of claim 20 wherein R.sub.2 is a C1-C6 alkyl
group, phenyl, benzyl or benzoyl; and R.sub.3 is --H or a C1-C6
alkyl group.
22. The compound of claim 21 wherein Ar is represented by the
following structural formula: 708wherein Phenyl Rings A' and A"
independently substituted or unsubstituted and Z is --O-- or
--CO--.
23. The compound of claim 22 wherein Phenyl Rings A' and A" are
independently substituted with one or more groups selected from
--R.sub.9, --OR.sub.9, --COR.sub.9, --COOR.sub.9, --CN, a
non-aromatic heterocyclic group, an alkyl group,
--(CH.sub.2).sub.aCH(OR.sub.30)(CH.su- b.2).sub.bCOOR.sub.31, or
--NR.sub.9C(O)R.sub.9, R.sub.9 is --H, a C1-C10 alkyl group, a
C1-C.sub.10 halogenated alkyl group, a cycloalkyl group or an
aromaotic group, R.sub.30 is a C1-C6 alkyl group or a halogenated
C1-C6 alkyl group, R.sub.31 is --H, a C1-C6 alkyl group or a
halogenated C1-C6 alkyl group, and a and b are independently 0, 1
or 2.
24. The compound of claim 23 wherein R.sub.2 is methyl and R.sub.3
is --H.
25. A compound represented by the following structural formula:
709or pharmaceutically acceptable salts, hydrates, stereoisomers
and solvates thereof, wherein Z is --O--, --CO--, --C(.dbd.NOH) or
a bond and t is 1, 2 or 3.
26. A compound represented by the following structural formula:
710or pharmaceutically acceptable salts, hydrates and solvates
thereof, wherein Z is --O--, --CO-- or a bond and t is 1, 2 or
3.
27. The compound of claim 2 wherein the compound is represented by
the following structural formula: 711wherein: p is zero, one or
two; W.sub.2 is --O--, --C(O)--, --OCH.sub.2--, --CH.sub.2--,
--NR.sub.8--, --NR.sub.8CO--, --NR.sub.8CH--, --C(.dbd.NOH)-- or
--CH(NR.sub.7R.sub.8)--; R.sub.7 and R.sub.8 are independently --H,
an aliphatic group, a substituted aliphatic group, an aromatic
group or a substituted aromatic group; and R.sub.11 and R.sub.12
are independently a C1-C6 alkyl group, or, taken together are a
substituted or unsubstituted ethylene, propylene or butylene
group.
28. The compound of claim 27 wherein W.sub.2 is --O--.
29. The compound of claim 28 wherein R.sub.1 is para to the carbon
atom bonded to W.sub.2 and is represented by the following
structural formula: 712wherein R.sub.2 is a C1-C6 alkyl group,
phenyl, benzyl or benzoyl; and R.sub.3 is --H or a C3-C6 alkyl
group.
30. The compound of claim 29 wherein Ar is represented by the
following structural formula: 713wherein Phenyl Rings A' and A"
independently substituted or unsubstituted and Z is --O-- or
--CO--.
31. The compound of claim 30 wherein Phenyl Rings A' and A" are
independently substituted with one or more groups selected from
--R.sub.9, --OR.sub.9, --COR.sub.9, --COOR.sub.9, --CN, a
non-aromatic heterocyclic group, an alkyl group,
--(CH.sub.2).sub.aCH(OR.sub.30)(CH.su- b.2).sub.bCOOR.sub.3, or
--NR.sub.9C(O)R.sub.9, and wherein R.sub.9 is --H, a C1-C10 alkyl
group, or a C1-C.sub.10 halogenated alkyl group, a cycloalkyl group
or an aromatic group, R.sub.30 is a C1-C6 alkyl group or a
halogenated C1-C6 alkyl group, R.sub.3, is --H, a C1-C6 alkyl group
or a halogenated C1-C6 alkyl group, and a and b are independently
0, 1 or 2.
32. The compound of claim 31 wherein R.sub.1 is represented by the
following structural formula: 714
33. The compound of claim 27 wherein: 1) p is one and R.sub.11 and
R.sub.12, taken together, are ethylene or propylene; 2) p is zero
and R.sub.11 and R.sub.12, taken together, are propylene or
butylene; or 3) p is zero, one or two and R.sub.11 and R.sub.12 are
independently methyl, ethyl or propyl.
34. The compound of claim 33 wherein Ar is represented by the
following structural formula: 715Phenyl Rings A, A' and A" are
unsubstituted and Z is --O--, --C(O)-- or a bond.
35. The compound of claim 2 wherein the compound is represented by
the following structural formula: 716wherein: W.sub.4 and W.sub.5
are independently methylene or ethylene; R.sub.2 is a C1-C6 alkyl
group, phenyl, benzyl or benzoyl; R.sub.3 is --H or a C1-C3 alkyl
group. R.sub.15 is H and R.sub.16 is a C1-C6 alkyl group, or
R.sub.15 and R.sub.16, taken together, are .dbd.O or
.dbd.CH.sub.2.
36. The compound of claim 35 wherein R.sub.15 is H and R.sub.16 is
methyl, ethyl or propyl, or R.sub.15 and R.sub.16, taken together,
are .dbd.O or .dbd.CH.sub.2.
37. A compound selected from the group consisting of
(S)-2-Methoxy-3-{4-[3-(4-phenoxy-phenoxy)-propoxy]-phenyl}-propionic
acid, represented by the following structural formula:
717(S)-3-{4-[3
(Biphenyl-4-yloxy)-propoxy]-phenyl}-2-methoxy-propionic acid,
represented by the following structural formula:
718(S)-3-{4-[3-(Biphenyl-4-yloxy)-p-
rop-1-ynyl]-phenyl}-2-methoxy-propionic acid, represented by the
following structural formula:
719(S)-3-{4-[3-(4-Benzoyl-phenoxy)-propoxy]-phenyl}--
2-methoxy-propionic acid, represented by the following structural
formula:
720(S)-3-(4-{3-[4-(4-Fluoro-benzoyl)-phenoxy]-propoxy}-phenyl)-2-methoxy-
-propionic acid, represented by the following structural formula:
721(S)-3-{4-[3-(4-Benzoyl-phenoxy)-propoxy]-3-methoxy-phenyl}-2-methoxy-p-
ropionic acid, which is represented by the following structural
formula:
722(S)-3-{4-[4-(Biphenyl-4-yloxy)-but-1-ynyl]-phenyl}-2-methoxy-propionic
acid, which is represented by the following structural formula:
723(S)-3-{4-[3-(4-Benzyl-phenoxy)-propoxy]-phenyl}-2-methoxy-propionic
acid, which is represented by the following structural formula:
724(S)-3-{4-[3-(4-Benzoyl-phenoxy)-prop-1-ynyl]-phenyl}-2-methoxy-propion-
ic acid, which is represented by the following structural formula:
725(S)-2-Methoxy-3-{4-[3-(4-phenoxy-phenoxy)-prop-1-ynyl]-phenyl}-propion-
ic acid, which is represented by the following structural formula:
726(S)-3-{4-[3-(Biphenyl-4-yloxy)-propoxy]-2-fluoro-phenyl}-2-methoxy-pro-
pionic acid, which is represented by the following structural
formula:
727(S)-3-{4-[3-(4-Butyl-phenoxy)-propoxy]-phenyl}-2-methoxy-propionic
acid, which is represented by the following structural formula:
728(S)-2-Methoxy-3-{4-[4-(4-phenoxy-phenoxy)-but-1-ynyl]-phenyl}-propioni-
c acid, which is represented by the following structural formula:
729(2S)-3-(4-{2-[4-(4-Fluoro-benzoyl)-phenoxy]-cyclopentyloxy}-phenyl)-2--
methoxy-propionic acid, which is represented by the following
structural formula:
730(S)-3-{4-[5-(Biphenyl-4-yloxy)-pent-1-ynyl]-phenyl}-2-methox-
y-propionic acid, which is represented by the following structural
formula:
731(S)-3-{4-[2-(4-Benzoyl-phenoxy)-ethoxy]-phenyl}-2-methoxy-pr-
opionic acid, which is represented by the following structural
formula:
732(S)-3-{4-[5-(Biphenyl-4-yloxy)-pentanoyl]-phenyl}-2-methoxy-propionic
acid, represented by the following structural formula:
733(S)-3-{4-[3-(Biphenyl-4-yloxy)-cyclopentyloxy]-phenyl}-2-methoxy-propi-
onic acid, represented by the following structural formula:
734(S)-3-{4-[4-(4-Benzoyl-phenoxy)-but-1-ynyl]-phenyl}-2-methoxy-propioni-
c acid, represented by the following structural formula:
735(S)-3-{4-[4-(4-Benzoyl-phenoxy)-butyryl]-phenyl}-2-methoxy-propionic
acid, represented by the following structural formula:
736(S)-2-Methoxy-3-{4-[5-(4-phenoxy-phenoxy)-pent-1-ynyl]-phenyl}-propion-
ic acid, represented by the following structural formula:
737(S)-3-{4-[5-(4-Benzoyl-phenoxy)-pent-1-ynyl]-phenyl}-2-methoxy-propion-
ic acid, represented by the following structural formula:
738(S)-3-{4-[3-(Biphenyl-4-yloxy)-propoxy]-3-methoxy-phenyl}-2-methoxy-pr-
opionic acid, represented by the following structural formula:
739(S)-2-Methoxy-3-{3-methoxy-4-[3-(4-phenoxy-phenoxy)-propoxy]-phenyl}-p-
ropionic acid, represented by the following structural formula:
740(S)-3-{4-[4-(4-Benzoyl-phenoxy)-butoxy]-phenyl}-2-methoxy-propionic
acid, represented by the following structural formula:
741(S)-3-{4-[5-(4-Benzoyl-phenoxy)-pentanoyl]-phenyl}-2-methoxy-propionic
acid, represented by the following structural formula:
742(S)-2-Methoxy-3-{4-[3-(4-phenylacetyl-phenoxy)-propoxy]-phenyl}-propio-
nic acid, represented by the following structural formula:
7432-Methoxy-3-(4-{3-[4-(4-trifluoromethyl-phenoxy)-phenoxy]-propoxy}-phe-
nyl)-propionic acid, represented by the following structural
formula:
7443-(4-{4-[4-(Hydroxyimino-phenyl-methyl)-phenoxy]-but-1-ynyl}-phenyl)-2-
-methoxy-propionic acid, represented by the following structural
formula:
7452-Methoxy-3-{4-[1-methyl-2-(4-phenoxy-phenoxy)-propoxy]-phenyl}-propio-
nic acid, represented by the following structural formula:
7463-{4-[2-(4-Benzoyl-phenoxy)-1-methyl-propoxy]-phenyl}-2-methoxy-propio-
nic acid, represented by the following structural formula:
747Sodium
3-{4-[3-(4-benzoyl-phenoxy)-propoxy]-phenyl}-2-methoxy-propionate,
represented by the following structural formula:
7483-{4-[3-(Biphenyl-4--
yloxy)-cyclopentyloxy]-phenyl}-(2S)-methoxy-propionic acid,
represented by the following structural formula:
7493-{4-[3-(Biphenyl-4-yloxy)-cyclopen-
tyloxy]-phenyl}-(2S)-methoxy-propionic acid, represented by the
following structural formula: 750Sodium
(S)-2-methoxy-3-{4-[6-(4-phenoxy-phenoxy)--
hex-1-ynyl]-phenyl}-propionate, represented by the following
structural formula: 751Sodium
(S)-3-{4-[6-(4-benzoyl-phenoxy)-hex-1-ynyl]-phenyl}-2-
-methoxy-propionate, represented by the following structural
formula: 752Sodium
(S)-3-{4-[6-(biphenyl-4-yloxy)-hex-1-ynyl]-phenyl}-2-methoxy-pr-
opionate, represented by the following structural formula:
753(S)-3-(4-{3-[4-(4-Hydroxy-benzoyl)-phenoxy]-propoxy}-phenyl)-2-methoxy-
-propionic acid, represented by the following structural formula:
754Sodium
(S)-2-methoxy-3-{4-[6-(4-phenoxy-phenoxy)-hexanoyl]-phenyl}-pro-
pionate, represented by the following structural formula:
755(S)-2-Methoxy-3-{4-[3-(9-oxo-9H-fluoren-2-yloxy)-prop-1-ynyl]-phenyl}--
propionic acid, represented by the following structural formula:
756(S)-2-Methoxy-3-{4-[3-(4-oxo-2-phenyl-4H-chromen-7-yloxy)-prop-1-ynyl]-
-phenyl}-propionic acid, represented by the following structural
formula:
757(S)-3-{4-[3-(4-Dibenzofuran-2-yl-phenoxy)-propoxy]-phenyl}-2-methoxy-p-
ropionic acid, represented by the following structural formula:
758(S)-3-{4-[3-(4'-tert-Butyl-biphenyl-4-yloxy)-propoxy]-phenyl}-2-methox-
y-propionic acid, represented by the following structural formula:
759(R)-2-Methoxy-3-{4-[3-(4-phenoxy-phenoxy)-propoxy]-phenyl}-propionic
acid, represented by the following structural formula: 760Sodium
(S)-2-methoxy-3-{4-[3-(4-phenylacetyl-phenoxy)-cyclopentyloxy]-phenyl}-pr-
opionate, represented by the following structural formula:
761Sodium
(S)-3-(4-{3-[4-(2-fluoro-benzoyl)-phenoxy]-propoxy}-phenyl)-2-methoxy-pro-
pionate, represented by the following structural formula:
762(S)-2-Methoxy-3-{2-methoxy-4-[3-(4-phenoxy-phenoxy)-propoxy]-phenyl}-p-
ropionic acid, represented by the following structural formula:
763Sodium
(S)-3-{4-[4-(4-benzoyl-phenoxy)-but-1-ynyl]-phenyl}-2-methoxy-propionate,
represented by the following structural formula: 764Sodium
(S)-3-{6-[3-(biphenyl-4-yloxy)-propoxy]-2'-methoxy-biphenyl-3-yl}-2-metho-
xy-propionate, represented by the following structural formula:
765Sodium
(S)-3-{4-[3-(4-benzoyl-phenoxy)-propoxy]-3-chloro-phenyl}-2-methoxy-propi-
onate, represented by the following structural formula: 766Sodium
(S)-2-methoxy-3-{4-[3-(4-oxo-2-phenyl-4H-chromen-6-yloxy)-prop-1-ynyl]-ph-
enyl}-propionate, represented by the following structural formula:
767(S)-3-{4-[3-(4'-Hydroxy-biphenyl-4-yloxy)-propoxy]-phenyl}-2-methoxy-p-
ropionic acid, represented by the following structural formula:
768Sodium
(S)-2-methoxy-3-(4-{3-[4-(4-trifluoromethyl-phenoxy)-phenoxy]-prop-1-ynyl-
}-phenyl)-propionate, represented by the following structural
formula:
769(S)-4'-{3-[4-(2-Carboxy-2-methoxy-ethyl)-phenoxy]-propoxy}-biphenyl-4--
carboxylic acid, represented by the following structural formula:
770Sodium
(S)-2-ethoxy-3-{4-[3-(4-phenoxy-phenoxy)-propoxy]-phenyl}-propi-
onate, represented by the following structural formula:
771(S)-2-Methoxy-3-{2-methoxy-4-[3-(4-phenoxy-phenoxy)-propoxy]-phenyl}-p-
ropionic acid 2-dimethylamino-ethyl ester, represented by the
following structural formula: 772Sodium
(S)-3-[4-(3-{4-[(4-fluoro-phenyl)-hydroxy--
methyl]-phenoxy}-propoxy)-phenyl]-2-methoxy-propionate, represented
by the following structural formula:
773(S)-2-Methoxy-3-(4-{3-[4-(naphthalene-1-
-carbonyl)-phenoxy]-propoxy}-phenyl)-propionic acid, represented by
the following structural formula:
774(S)-2-Methoxy-3-(4-{3-[4-(4-methyl-benz-
oyl)-phenoxy]-propoxy}-phenyl)-propionic acid, represented by the
following structural formula:
775(S)-2-Methoxy-3-(4-{3-[4-(3-phenyl-prop-
ionyl)-phenoxy]-propoxy}-phenyl)-propionic acid, represented by the
following structural formula:
776(S)-3-(4-{3-[4-(2,4-Dimethoxy-benzoyl)--
phenoxy]-propoxy}-phenyl)-2-methoxy-propionic acid, represented by
the following structural formula:
777(S)-3-{3-Chloro-4-[3-(4-oxo-2-phenyl-4H-
-chromen-6-yloxy)-propoxy]-phenyl}-2-methoxy-propionic acid,
represented by the following structural formula:
778(S)-3-{4-[3-(4-Benzoyl-phenoxy)--
propoxy]-2-chloro-phenyl}-2-methoxy-propionic acid, represented by
the following structural formula:
779(S)-2-Methoxy-3-(3-methoxy-4-{3-[4-(4-t-
rifluoromethyl-phenoxy)-phenoxy]-propoxy}-phenyl)-propionic acid,
represented by the following structural formula:
780(S)-2-Methoxy-3-(4-{-
3-[4-(3-methyl-butoxy)-phenoxy]-propoxy}-phenyl)-propionic acid,
represented by the following structural formula:
781(S)-2-Methoxy-3-{4-[-
3-(4-pyridin-4-yl-phenoxy)-propoxy]-phenyl}-propionic acid,
represented by the following structural formula:
782(S)-2-Methoxy-3-{4-[3-(4-phenethylo-
xy-phenoxy)-propoxy]-phenyl}-propionic acid, represented by the
following structural formula:
7833-{4-[3-(4-Benzoyl-phenoxy)-propoxy]-2-chloro-phe-
nyl}-2-methoxy-propionic acid, represented by the following
structural formula: 784Sodium
(S)-3-{4-[3-(biphenyl-4-yloxy)-cyclohexyloxy]-phenyl}-
-2-methoxy-propionate, represented by the following structural
formula: 785Sodium
(S)-3-{4-[3-(2-carboxy-phenoxy)-propoxy]-phenyl}-2-methoxy-prop-
ionate, represented by the following structural formula:
7862-Methoxy-3-{2-methoxy-4-[3-(4-phenoxy-phenoxy)-propoxy]-phenyl}-propi-
onic acid, represented by the following structural formula:
787(S)-2-Methoxy-3-{4-[3-(4-quinolin-8-yl-phenoxy)-propoxy]-phenyl}-propi-
onic acid, represented by the following structural formula:
788(S)-2-Methoxy-3-(4-{3-[4'-(1H-tetrazol-5-yl)-biphenyl-4-yloxy]-propoxy-
}-phenyl)-propionic acid, represented by the following structural
formula:
7893-{4-[3-(4-phenoxy-phenoxy)-propoxy]-phenyl}-2-propoxy-propionic
acid, represented by the following structural formula:
7903-{4-[3-(4-Benzoyl-phenoxy)-propoxy]-phenyl}-2-ethoxy-propionic
acid, represented by the following structural formula:
791(S)-2-Isopropoxy-3-{-
4-[3-(4-phenoxy-phenoxy)-propoxy]-phenyl}-propionic acid,
represented by the following structural formula:
792(S)-3-{4-[3-(4-Benzyl-phenoxy)-prop-
oxy]-phenyl}-2-ethoxy-propionic acid, represented by the following
structural formula:
793(S)-3-{4-[3-(4-Benzoyl-phenoxy)-propoxy]-3-chloro-
-phenyl}-2-ethoxy-propionic acid, represented by the following
structural formula:
794(S)-2-Methoxy-3-{4-[3-(4-morpholin-4-yl-phenoxy)-propoxy]-ph-
enyl}-propionic acid, represented by the following structural
formula:
795(S)-3-{4-[2-(Biphenyl-4-yloxy)-ethoxy]-phenyl}-2-methoxy-propionic
acid, represented by the following structural formula:
796(S)-2-Methoxy-3-{4-[3-(5,6,7,8-tetrahydro-naphthalen-2-yloxy)-propoxy]-
-phenyl}-propionic acid, represented by the following structural
formula:
797(S)-2-Methoxy-3-{4-[2-(4-phenoxy-phenoxy)-ethoxy]-phenyl}-propionic
acid, represented by the following structural formula:
7983-{3-[3-(Biphenyl-4-yloxy)-propoxy]-phenyl}-2-methoxy-propionic
acid, represented by the following structural formula:
799(S)-3-{4-[3-(3-Dimet-
hylamino-phenoxy)-propoxy]-phenyl}-2-methoxy-propionic acid,
represented by the following structural formula:
800(S)-3-{4-[2-(Biphenyl-4-yloxy)-e-
thoxy]-phenyl}-2-ethoxy-propionic acid, represented by the
following structural formula: 801and
(S)-3-{4-[2-(Biphenyl-4-yloxy)-ethoxy]-phenyl-
}-2-propoxy-propionic acid, represented by the following structural
formula: 802or a pharmaceutically acceptable salts, hydrates and
solvates of the foregoing compounds.
38. A compound represented by the following structural formula:
803or pharmaceutically acceptable salts, hydrates, stereoisomers
and solvates thereof, wherein: Ar is a substituted or unsubstituted
aromatic group; R.sub.1 is
--(CH.sub.2).sub.n--CH(OR.sub.2)--(CH.sub.2).sub.mE,
--(CH).dbd.C(OR.sub.2)--(CH.sub.2).sub.mE, --(CH.sub.2),
--CH(Y)--(CH.sub.2).sub.mE or --(CH).dbd.C(Y)--(CH.sub.2).sub.mE;
wherein E is COOR.sub.3, C.sub.1-C.sub.3-alkylnitrile, carboxamide,
sulfonamide, acylsulfonamide or tetrazole and wherein sulfonamide,
acylsulfonamide and tetrazole are optionally substituted with one
or more substituents independently selected from: C1-C6 alkyl,
haloalkyl and aryl-C0-4-alkyl; R.sub.2 is --H, an aliphatic group,
a substituted aliphatic group, an aromatic group, a substituted
aromatic group, --COR.sub.4, --COOR.sub.4, --CONR.sub.5R.sub.6,
--C(S)R.sub.4, --C(S)OR.sub.4 or --C(S)NR.sub.5R.sub.6; Y is --O--,
--CH.sub.2--, --CH.sub.2CH.sub.2-- or --CH.dbd.CH-- and is bonded
to a carbon atom in Phenyl Ring A that is ortho to R.sub.1;
R.sub.3-R.sub.6 are independently --H, an aliphatic group, a
substituted aliphatic group, an aromatic group or a substituted
aromatic group; n and m are independently 0, 1 or 2; s is 0, 1 or
2; Ar.sub.1 is a substituted or unsubstituted arylene group;
W.sub.6 is a covalent bond, --W.sub.1--, --CH.sub.2W.sub.1-- or
--W.sub.1CH.sub.2--; W.sub.7 is a covalent bond or CH.sub.2--; and
W.sub.1 is --O--, --C(O)--, --OCH.sub.2--, --CH.sub.2--,
--NR.sub.8--, --NR.sub.8CO--, --NR.sub.8CH--, --C(.dbd.NOH)-- or
--CH(NR.sub.7R.sub.8)--.
39. The compound of claim 38 wherein R.sub.1 is
--(CH.sub.2).sub.n--CH(OR.- sub.2)--(CH.sub.2).sub.mCOOR.sub.3,
--(CH).dbd.C(OR.sub.2)--(CH.sub.2).sub- .mCOOR.sub.3,
--(CH.sub.2).sub.n--CH(Y)--(CH.sub.2).sub.mCOOR.sub.3 or
--(CH).dbd.C(Y)--(CH.sub.2).sub.mCOOR.sub.3.
40. The compound of claim 39 wherein the compound is represented by
the following structural formula: 804wherein s is 0 or 1 and
W.sub.6 is a covalent bond, --O--, --CH.sub.2O-- or
--OCH.sub.2--.
41. A pharmaceutical composition comprising the compound of claim 1
and a pharmaceutically acceptable carrier.
42. The pharmaceutical composition of claim 41 additionally
comprising a second therapeutic agent selected from the group
consisting of insulin sensitizers, sulfonylureas, biguanides,
thiazolidinediones, .alpha.-glucosidase inhibitors, insulin
secretogogues, insulin, antihyperlipidemic agents, plasma
HDL-raising agents, HMG-CoA reductase inhibitors, statins, acyl
CoA:cholesterol acyltransferase inhibitors, antiobesity compounds,
antihypercholesterolemic agents, fibrates, vitamins and
aspirin.
43. A pharmaceutical composition comprising the compound of claim 2
and a pharmaceutically acceptable carrier.
44. A pharmaceutical composition comprising: 1) the compound of
claim 2 or a pharmaceutically acceptable salt, solvate, hydrate or
stereoisomer thereof; a second therapeutic agent selected from the
group consisting of insulin sensitizers, sulfonylureas, biguanides,
thiazolidinediones, .alpha.-glucosidase inhibitors, insulin
secretogogues, insulin, antihyperlipidemic agents, plasma
HDL-raising agents, HMG-CoA reductase inhibitors, statins, acyl
CoA:cholesterol acyltransferase inhibitors, antiobesity compounds,
antihypercholesterolemic agents, fibrates, vitamins and aspirin;
and 3) a pharmaceutically acceptable carrier.
45. A pharmaceutical composition comprising the compound of claim
18 or a pharmaceutically acceptable salt, solvate or hydrate
thereof, and a pharmaceutically acceptable carrier.
46. The pharmaceutical composition of claim 45 additionally
comprising a second therapeutic agent selected from the group
consisting of insulin sensitizers, sulfonylureas, biguanides,
thiazolidinediones, .alpha.-glucosidase inhibitors, insulin
secretogogues, insulin, antihyperlipidemic agents, plasma
HDL-raising agents, HMG-CoA reductase inhibitors, statins, acyl
CoA:cholesterol acyltransferase inhibitors, antiobesity compounds,
antihypercholesterolemic agents, fibrates, vitamins and
aspirin.
47. A method of modulating a peroxisome proliferator activated
receptor (PPAR), comprising the step of contacting the receptor
with at least one compound of claim 1.
48. The method of claim 47, wherein the PPAR is an alpha
receptor.
49. The method of claim 47, wherein the PPAR is an gamma
receptor.
50. A method of modulating a peroxisome proliferator activated
receptor (PPAR), comprising the step of contacting the receptor
with at least one compound of claim 2.
51. A method of modulating a peroxisome proliferator activated
receptor (PPAR), comprising the step of contacting the receptor
with the compound of claim 18.
52. A method for treating a PPAR-gamma mediated disease or
condition in a subject comprising the step of administering to the
subject an effective amount of the compound claim 1.
53. A method for treating a PPAR-gamma mediated disease or
condition in a subject comprising the step of administering to the
subject an effective amount of the compound claim 2.
54. A method for treating a PPAR-gamma mediated disease or
condition in a subject comprising the step of administering to the
subject an effective amount of the compound claim 18.
55. A method for lowering blood-glucose in a subject comprising the
step of administering to the subject an effective amount of the
compound of claim 1.
56. A method for lowering blood-glucose in a subject comprising the
step of administering to the subject an effective amount of the
compound of claim 2.
57. A method for lowering blood-glucose in a subject comprising the
step of administering to the subject an effective amount of the
compound of claim 18.
58. A method of treating a subject with hyperglycemia,
dyslipidemia, Type II diabetes, Type I diabetes,
hypertriglyceridemia, syndrome X, insulin resistance, heart
failure, diabetic dyslipidemia, hyperlipidemia, hypercholesteremia,
hypertension, obesity, anorexia bulimia, polycystic ovarian
syndrome, anorexia nervosa, cardiovascular disease or other
diseases where insulin resistance is a component, said method
comprising the step of administering to the subject an effective
amount of the compound of claim 1.
59. A method of treating a subject with hyperglycemia,
dyslipidemia, Type II diabetes, Type I diabetes,
hypertriglyceridemia, syndrome X, insulin resistance, heart
failure, diabetic dyslipidemia, hyperlipidemia, hypercholesteremia,
hypertension, obesity, anorexia bulimia, polycystic ovarian
syndrome, anorexia nervosa, cardiovascular disease or other
diseases where insulin resistance is a component, said method
comprising the step of administering to the subject an effective
amount of the compound of claim 2.
60. A method of treating a subject with hyperglycemia,
dyslipidemia, Type II diabetes, Type I diabetes,
hypertriglyceridemia, syndrome X, insulin resistance, heart
failure, diabetic dyslipidemia, hyperlipidemia, hypercholesteremia,
hypertension, obesity, anorexia bulimia, polycystic ovarian
syndrome, anorexia nervosa, cardiovascular disease or other
diseases where insulin resistance is a component, said method
comprising the step of administering to the subject an effective
amount of the compound of claim 18.
61. The method of claim 58 additionally comprising the step of
administering to the subject an effective amount of second
therapeutic agent selected from the group consisting of insulin
sensitizers, sulfonylureas, biguanides, thiazolidinediones,
.alpha.-glucosidase inhibitors, insulin secretogogues, insulin,
antihyperlipidemic agents, plasma HDL-raising agents, HMG-CoA
reductase inhibitors, statins, acyl CoA:cholesterol acyltransferase
inhibitors, antiobesity compounds, antihypercholesterolemic agents,
fibrates, vitamins and aspirin.
62. The method of claim 59 additionally comprising the step of
administering to the subject an effective amount of second
therapeutic agent selected from the group consisting of insulin
sensitizers, sulfonylureas, biguanides, thiazolidinediones,
.alpha.-glucosidase inhibitors, insulin secretogogues, insulin,
antihyperlipidemic agents, plasma HDL-raising agents, HMG-CoA
reductase inhibitors, statins, acyl CoA:cholesterol acyltransferase
inhibitors, antiobesity compounds, antihypercholesterolemic agents,
fibrates, vitamins and aspirin.
63. The method of claim 60 additionally comprising the step of
administering to the subject an effective amount of second
therapeutic agent selected from the group consisting of insulin
sensitizers, sulfonylureas, biguanides, thiazolidinediones,
.alpha.-glucosidase inhibitors, insulin secretogogues, insulin,
antihyperlipidemic agents, plasma HDL-raising agents, HMG-CoA
reductase inhibitors, statins, acyl CoA:cholesterol acyltransferase
inhibitors, antiobesity compounds, antihypercholesterolemic agents,
fibrates, vitamins and aspirin.
64. A method of treating a subject with diabetes mellitus, said
method comprising the step of administering to the subject an
effective amount of the compound of claim 1.
65. A method of treating a subject with diabetes mellitus, said
method comprising the step of administering to the subject an
effective amount of the compound of claim 2.
66. A method of treating a subject with diabetes mellitus, said
method comprising the step of administering to the subject an
effective amount of the compound of claim 18.
67. A method of treating a subject with cardiovascular disease,
said method comprising the step of administering to the subject an
effective amount of the compound of claim 1.
68. A method of treating a subject with cardiovascular disease,
said method comprising the step of administering to the subject an
effective amount of the compound of claim 2.
69. A method of treating a subject with cardiovascular disease,
said method comprising the step of administering to the subject an
effective amount of the compound of claim 18.
70. A method of treating a subject with Syndrome X, said method
comprising the step of administering to the subject an effective
amount of the compound of claim 1.
71. A method of treating a subject with Syndrom X, said method
comprising the step of administering to the subject an effective
amount of the compound of claim 2.
72. A method of treating a subject with Syndrome X, said method
comprising the step of administering to the subject an effective
amount of the compound of claim 18.
73. A method of preparing a compound represented by the following
structural formula: 805from a starting compound represented by the
following structural formula: 806said method comprising the step of
hydrolyzing the ester group in the starting compound, wherein: Ar
is a substituted or unsubstituted aromatic group; Q is a covalent
bond, --CH.sub.2-- or --CH.sub.2CH.sub.2--; W is a substituted or
unsubstituted alkylene or heteroalkylene linking group from two to
ten atoms in length; phenyl Ring A is optionally substituted with
up to four substituents in addition to W and
--CH.sub.2CHOR.sub.2C(O)OR.sub.3; R.sub.2 is --H, an aliphatic
group, a substituted aliphatic group, an aromatic group, a
substituted aromatic group; R.sub.3 an aliphatic group, a
substituted aliphatic group, an aromatic group or a substituted
aromatic group.
74. The method of claim 73 wherein Q is a covalent bond.
75. The method of claim 74 wherein the starting compound is
represented by the following structural formula: 807i. p is an
integer from one to four; W.sub.1 is --O--, --C(O)--,
--OCH.sub.2--, --CH.sub.2--, --NR.sub.8--, --NR.sub.8CO--,
--NR.sub.8CH--, --C(.dbd.NOH)-- or --CH(NR.sub.7R.sub.8)--; R.sub.2
is a C1-C6 alkyl group, phenyl, benzyl or benzoyl; R.sub.3--H or a
C1-C3 alkyl group; and R.sub.7 and R.sub.8 are independently --H,
an aliphatic group, a substituted aliphatic group, an aromatic
group or a substituted aromatic group.
76. The method of claim 75 wherein the compound is represented by
the following structural formula: 808wherein: Phenyl Rings A' and
A" independently substituted or unsubstituted and Z is --O-- or
--CO--.
77. The method of claim 76 wherein the compound is represented by
the following structural formula: 809
78. A compound, wherein the compound is radiolabeled
(S)-3-{4-[3-(Biphenyl-4-yloxy)-propoxy]-phenyl}-2-methoxy-propionic
acid, represented by the following structural formula: 810
79. The compound of claim 78 wherein the radiolabel is a tritium
atom.
80. A method for determining whether a compound does or does not
interact directly with peroxisome proliferator-activated receptor,
comprising the step of specifically binding the radiolabeled
compound of claim 78 to the ligand binding domain of the peroxisome
proliferator-activated receptor.
81. The method of claim 80 wherein the peroxisome
proliferator-activated receptor is PPAR.gamma..
82. The method of claim 81 additionally comprising the step of
contacting the receptor with a test compound and assessing the
amount of specific binding of the radiolabeled compound to the
receptor, wherein a decrease in the binding of the radiolabeled
compound indicates that the test compound interacts directly with
the peroxisome proliferator-activated receptor.
83. The method of claim 82 wherein the radiolabeled compound is
tritiated.
Description
RELATED APPLICATIONS
[0001] This application claims the benefit of U.S. provisional
application 60/297,144, filed 7 Jun. 2001, the entire teachings of
which are incorporated herein by reference.
BACKGROUND OF THE INVENTION
[0002] The peroxisome proliferator activated receptors (PPARs) are
members of the nuclear receptor gene family that are activated by
fatty acids and fatty acid metabolites. The PPARs belong to the
subset of nuclear receptors that function as heterodimers with the
9-cis retinoic acid receptor (RXR). Three subtypes, designated
PPAR.alpha., PPAR.gamma. and PPAR.delta., are found in species
ranging from Xenopus to humans.
[0003] PPAR.alpha. is the main subtype in the liver and has
facilitated analysis of the mechanism by which peroxisome
proliferators exert their pleiopropic effects. PPAR.alpha. is
activated by a number of medium and long-chain fatty acids, and it
is involved in stimulating .beta.-oxidation of fatty acids.
PPAR.alpha. is also involved with the activity of fibrates and
fatty acids in rodents and humans. Fibric acid derivatives such as
clofibrate, fenofibrate, bezafibrate, ciprofibrate, beclofibrate
and etofibrate, as well as gemfibrozil, produce a substantial
reduction in plasma triglycerides along with moderate reduction in
low-density lipoprotein (LDL) cholesterol, and they are used
particularly for the treatment of hypertriglyceridemia.
[0004] PPAR.gamma. is the main subtype in adipose tissue and
involved in activating the program of adipocyte differentiation.
PPAR.gamma. is not involved in stimulating peroxisome proliferation
in the liver. There are two isomers of PPAR.gamma.: PPAR.gamma.1
and PPAR.gamma.2, which differ only in that PPAR.gamma.2 conatins
an additional 28 amino acids present at the amino terminus. The DNA
sequences for the PPAR.gamma. receptors are described in Elbrecht,
et al., BBRC 224;431-437 (1996). Although peroxisome proliferators,
including the fibrates and fatty acids, activate the
transcriptional activity of PPAR's, only prostaglandin J.sub.2
derivatives have been identified as natural ligands for
PPAR.gamma., which also binds the anti-diabetic agents
thiazolidinediones with high affinity. The physiological functions
of PPAR.alpha. and PPAR.gamma. in lipid and carbohydrate metabolism
were uncovered once it was recognized that they were the receptors
for the fibrate and glitazone drugs, respectively.
[0005] PPAR.alpha. and PPAR.gamma. receptors have been implicated
in diabetes mellitus, cardiovascular disease, obesity, and
gastrointestinal disease, such as inflammatory bowel disease and
other inflammation related illnesses. Such inflammation related
illnesses include, but are not limited to Alzheimer's disease,
Crohn's disease, rheumatoid arthritis, psoriasis, and ischemia
reprofusion injury. By contrast, PPAR.delta. (also referred to as
PPAR.beta. and NUC1) is not reported to be receptor for any known
class of drug molecules, and its role in mammalian physiology has
remained undefined. The human nuclear receptor gene PPAR.delta.
(hPPAR.delta.) has been cloned from a human osteosarcoma cell cDNA
library and is fully described in A. Schmidt et al., Molecular
Endocrinology, 6:1634-1641 (1992).
[0006] Diabetes is a disease in which a mammal's ability to
regulate glucose levels in the blood is impaired because the mammal
has a reduced ability to convert glucose to glycogen for storage in
muscle and liver cells. In Type I diabetes, this reduced ability to
store glucose is caused by reduced insulin production. "Type II
Diabetes" or "non-insulin dependent diabetes mellitus" (NIDDM) is
the form of diabetes, which is due to a propound resistance to
insulin stimulating or regulatory effect on glucose and lipid
metabolism in the main insulin-sensitive tissues, muscle, liver and
adipose tissue. This resistance to insulin responsiveness results
in insufficient insulin activation of glucose uptake, oxidation and
storage in muscle and inadequate insulin repression of lipolysis in
adipose tissue and of glucose production and secretion in liver.
When these cells become desensitized to insulin, the body tries to
compensate by producing abnormally high levels of insulin and
hyperinsulemia results. Hyperinsulemia is associated with
hypertension and elevated body weight. Since insulin is involved in
promoting the cellular uptake of glucose, amino acids and
triglycerides from the blood by insulin sensitive cells, insulin
insensitivity can result in elevated levels of triglycerides and
LDL (known as the "bad" cholesterol) which are risk factors in
cardiovascular diseases. The constellation of symptoms which
includes hyperinsulemia combined with hypertension, elevated body
weight, elevated triglycerides and elevated LDL is known as
Syndrome X.
[0007] Hyperlipidemia is a condition which is characterized by an
abnormal increase in serum lipids, such as cholesterol,
triglycerides and phospholipids. These lipids do not circulate
freely in solution in plasma, but are bound to proteins and
transported as macromolecular complexes called lipoproteins. One
form of hyperlipidemia is hypercholesterolemia, characterized by
the existence of elevated LDL cholesterol levels. The initial
treatment for hypercholesterolemia is often a diet low in fat and
cholesterol coupled with appropriate physical exercise. Drug
intervention is initiated if LDL-lowering goals are not met by diet
and exercise alone. It is desirable to lower elevated levels of LDL
cholesterol and increase levels of HDL cholesterol. Generally, it
has been found that increased levels of HDL are associated with
lower risk for coronary heart disease (CHD). See Gordon, et al.,
Am. J. Med., 62, 707-714 (1977); Stampfer, et al., N. England J.
Med., 325, 373-381 (1991); and Kannel, et al., Ann. Internal Med.,
90, 85-91 (1979). An example of an HDL raising agent is nicotinic
acid, but the quantities needed to achieve HDL elevation are
associated with undesirable effects, such as flushing.
[0008] There are several treatments currently available for
treating diabetes mellitus but these treatments still remain
unsatisfactory and have limitations. While physical exercise and
reduction in dietary intake of calories will improve the diabetic
condition, compliance with this approach can be poor because of
sedentary lifestyles and excess food consumption, in particular
high fat-containing food. Therefore treatment with hypoglycemics,
such as sulfonylureas (e.g., chlorpropamide, tolbutamide,
tolazamide and acetohexamide) and biguanides (e.g. phenformin and
metformin) are often necessary as the disease progresses.
Sulfonylureas stimulate the .beta. cells of the pancreas to secrete
more insulin as the disease progresses. However, the response of
the .beta. cells eventually fails and treatment with insulin
injections is necessary. In addition, both sulfonylurea treatment
and insulin injection have the life threatening side effect of
hypoglycemic coma, and thus patients using these treatments must
carefully control dosage.
[0009] It has been well established that improved glycemic control
in patients with diabetes (Type I and Type II) is accompanied by
decreased microvasclular complications (DCCT and UKPDS). Due to
difficulty in maintaining adequate glycemic control over time in
patients with Type II diabetes, the use of insulin sensitizers in
the therapy of Type II diabetes is growning. There is also a
growing body of evidence that PPAR.gamma. agonist, insulin
sensitizer, may have benefits in the treatment of Type II diabetes
beyond their effects in improving glycemic control.
[0010] In the last decade a class of compounds known as
thiazolidinediones (e.g. U.S. Pat. Nos. 5,089,514; 4,342,771;
4,367,234; 4,340,605; and 5,306,726) have emerged as effective
anidiabetic agents that have been shown to increase the sensitivity
of insulin sensitive tissues, such as skeletal muscle, liver and
adipose, to insulin. Increasing insulin sensitivity rather than the
amount of insulin in the blood reduces the likelihood of
hypoglycemic coma. Although thiazolidinediones have been shown to
increase insulin sensitivity by binding to PPAR.gamma. receptors,
this treatment also produces unwanted side effects such as weight
gain and, for troglitazone, liver toxicity.
[0011] In view of the above, there exists a need for new
pharmaceutical agents which modulate these receptors to prevent,
treat and/or alleviate these diseases or conditions while
ameliorating side effects of current treatments.
SUMMARY OF THE INVENTION
[0012] Disclosed herein are novel .alpha.-methoxy cinnamates which
are modulators of peroxisome proliferator activated receptors
(PPAR). Many of these novel .alpha.-methoxy cinnamates have the
advantage over previously known PPAR modulators in that they
selectively bind at peroxisome proliferator activated receptor
modulators. Based on this discovery, methods of modulating a
peroxisome proliferator activated receptor in a subject in need of
such modulation, methods of treating a subject for Type II
diabetes, methods of treating a subject for cardiovascular disease,
methods of treating a subject for Syndrome X and methods of
treating a subject with other PPAR-mediated diseases and conditions
are disclosed herein.
[0013] One embodiment of the present invention is a compound
represented by Structural Formula (I): 2
[0014] The variables in Structural Formula (I) are defined
below.
[0015] Ar is a substituted or unsubstituted aromatic group.
Preferably, Ar is an unsubstituted, monosubstituted or
disubstituted aromatic group.
[0016] Q is a covalent bond, --CH.sub.2--, --CH.sub.2CH.sub.2--,
--CH.sub.2CH.sub.2CH.sub.2-- or
--CH.sub.2CH.sub.2CH.sub.2CH.sub.2--. Preferably, Q is a covalent
bond.
[0017] W is a substituted or unsubstituted alkylene group two to
ten atoms in length or a substituted or unsubstituted
heteroalkylene group, wherein the heteroalkylene group is an
alkylene group from two to ten atoms in length in which one or more
methylene groups have been replaced with a functional group
selected from --CH.dbd.CH--, --C.ident.C--, --O--, --CO--,
--NR.sub.7--, --NR.sub.7CO--, --C(.dbd.NOH)--, --S--, --S(O)--,
--S(O).sub.2-- or --CH(NR.sub.7R.sub.8)--.
[0018] Phenyl Ring A is optionally substituted with up to four
substituents in addition to R.sub.1 and W.
[0019] R.sub.1 is
(CH.sub.2).sub.n--CH(OR.sub.2)--(CH.sub.2).sub.mE,
--(CH).dbd.C(OR.sub.2)--(CH.sub.2).sub.mE,
--(CH.sub.2).sub.n--CH(Y)--(CH- .sub.2).sub.mE or
--(CH).dbd.C(Y)--(CH.sub.2).sub.mE. E is COOR.sub.3,
C1-C3-alkylnitrile, carboxamide, sulfonamide, acylsulfonamide or
tetrazole and wherein sulfonamide, acylsulfonamide and tetrazole
are optionally substituted with one or more substituents
independently selected from: C1-C6 alkyl, C1-C6 haloalkyl and
aryl-C0-4-alkyl. Preferably R.sub.1 is
--(CH.sub.2).sub.n--C(OR.sub.2)--(CH.sub.2).sub.mCO- OR.sub.3,
--(CH).dbd.C(OR.sub.2)--(CH.sub.2).sub.mCOOR.sub.3,
--(CH.sub.2).sub.n--CH(Y)--(CH.sub.2).sub.mCOOR.sub.3 or
--(CH).dbd.C(Y)--(CH.sub.2).sub.mCOOR.sub.3. More preferably
R.sub.1 is meta or para to W and is represented by Structural
Formula (II), even more preferably by Structural Formulas (III) or
(IV) and even more preferably by Structural Formula (V): 3
[0020] R.sub.2 is --H, an aliphatic group, a substituted aliphatic
group, haloalkyl, an aralkyl group, a substituted aralkyl group, an
aromatic group, a substituted aromatic group, --COR.sub.4,
--COOR.sub.4, --CONR.sub.5R.sub.6, --C(S)R.sub.4, --C(S)OR.sub.4 or
--C(S)NR.sub.5R.sub.6.
[0021] Y is --O--, --CH.sub.2--, --CH.sub.2CH.sub.2-- or a
--CH.dbd.CH-- group that is bonded to a carbon atom in Phenyl Ring
A that is ortho to R.sub.1. Thus, Y, together with the two carbon
atoms to which Y is bonded and the intervening carbon atoms, form a
ring that is fused to Phenyl Ring A.
[0022] R.sub.3-R.sub.8 are independently --H, an aliphatic group, a
substituted aliphatic group, an aromatic group or a substituted
aromatic group.
[0023] n and m are independently 0, 1 or 2.
[0024] In Structural Formula (I), preferably, R.sub.2 is a C1-C6
lower alkyl group, phenyl, benzyl or benzoyl; and R.sub.3 is --H or
a C1-C6 alkyl group (more preferably C1-C3 alkyl group).
[0025] In another embodiment, the compound of the present invention
is represented by Structural Formula (VI): 4
[0026] The variables in Structural Formula (VI) are defined
below.
[0027] Ar is a substituted or unsubstituted aromatic group.
Preferably, Ar is an unsubstituted, monosubstituted or
disubstituted aromatic group.
[0028] W is a substituted or unsubstituted alkylene linking group
or a substituted or unsubstituted heteroalkylene linking group from
two to ten atoms in length, preferably from two to seven atoms in
length.
[0029] Phenyl Ring A is optionally substituted with up to four
substituents in addition to R.sub.1.
[0030] R.sub.1 is
--(CH.sub.2).sub.n--CH(OR.sub.2)--(CH.sub.2).sub.mCOOR.s- ub.3,
--(CH).dbd.C(OR.sub.2)--(CH.sub.2).sub.mCOOR.sub.3,
--(CH.sub.2).sub.nCH(Y)--(CH.sub.2).sub.mCOOR.sub.3 or
--(CH).dbd.C(Y)--(CH.sub.2).sub.mCOOR.sub.3. Preferably R.sub.1 is
meta or para to W and is represented by Structural Formula (II),
more preferably by Structural Formula (III) and even more
preferably by Structural Formula (IV). Structural Formulas (II)-(V)
are shown above.
[0031] R.sub.2 is --H, an aliphatic group, a substituted aliphatic
group, an aryl group, a substituted aryl group, --COR.sub.4,
--COOR.sub.4, --CONR.sub.5R.sub.6, --C(S)R.sub.4, --C(S)OR.sub.4 or
--C(S)NR.sub.5R.sub.6.
[0032] Y is --O--, --CH.sub.2--, --CH.sub.2CH.sub.2-- or
--CH.dbd.CH-- and is bonded to a carbon atom in Phenyl Ring A that
is ortho to R.sub.1.
[0033] R.sub.3-R.sub.6 are independently --H, an aliphatic group, a
substituted aliphatic group, an aryl group or a substituted aryl
group.
[0034] n and m are independently 0, 1 or 2.
[0035] In Structural Formula (VI), preferably, R.sub.2 is a C1-C6
lower alkyl group, phenyl, benzyl or benzoyl; and R.sub.3 is --H or
a C1-C3 lower alkyl group.
[0036] Another embodiment of the present invention is a method of
modulating a peroxisome proliferator activated receptor (PPAR). The
method comprises the step of contacting the receptor with at least
one of the compounds of the present invention.
[0037] Another embodiment of the present invention is a method of
modulating a peroxisome proliferator activated receptor gamma in a
subject in need of modulation of the peroxisome proliferator
activated receptor gamma, i.e., treating a PPAR-gamma mediated
disease in a subject. The method comprises the step of
administering to the subject an effective amount of a compound of
the present invention.
[0038] Another embodiment of the present invention is a method for
lowering blood-glucose in a subject in need of such treatment. The
method comprises the step of administering to the subject an
effective amount of a compound of the present invention.
[0039] Another embodiment of the present invention is a method of
treating a subject for hyperglycemia, dyslipidemia, Type II
diabetes, Type I diabetes, hypertriglyceridemia, syndrome X,
insulin resistance, heart failure, diabetic dyslipidemia,
hyperlipidemia, hypercholesteremia, hypertension, obesity, anorexia
bulimia, polycystic ovarian syndrome, anorexia nervosa,
cardiovascular disease or other diseases where insulin resistance
is a component. The method comprises the step of administering to
the subject an effective amount of a compound of the present
invention.
[0040] Another embodiment of the present invention is a method of
treating a subject with diabetes mellitus. The method comprises the
step of administering to the subject an effective amount of a
compound of the present invention
[0041] Another embodiment of the present invention is a method of
treating a subject for cardiovascular disease. The method comprises
the step of administering to the subject an effective amount of a
compound of the present invention.
[0042] Another embodiment of the present invention is a method of
treating a subject for Syndrome X. The method comprises the step of
administering to the subject an effective amount of a compound of
the present invention.
[0043] Another embodiment of the present invention is a compound of
the present invention for use in therapy. The therapy can be, for
example, to treat Type II diabetes, cardiovascular disease,
Syndrome X or a disorder modulated by a peroxisome proliferator
activated receptor.
[0044] Another embodiment of the present invention is the use of a
compound of the present invention for the manufacture of a
medicament for the treatment of hyperglycemia, dyslipidemia, Type
II diabetes, Type I diabetes, hypertriglyceridemia, syndrome X
insulin resistance, heart failure, diabetic dyslipidemia,
hyperlipidemia, hypercholesteremia, hypertension, obesity, anorexia
bulimia, polycystic ovarian syndrome, anorexia nervosa,
cardiovascular disease or other diseases where insulin resistance
is a component or other disorders modulated by a peroxisome
proliferator activated receptor.
[0045] Yet another embodiment of the present invention is a
pharmaceutical composition which comprises a pharmaceutically
acceptable carrier and at least one compound of the present
invention.
[0046] Yet another embodiment of the present invention is a method
of preparing a compound represented by Structural Formula (VII)
from a starting compound represented by Structural Formula (VIII):
5
[0047] The method comprises the step of hydrolyzing the ester group
in the starting compound. Phenyl Ring A, Ar, Q, W, R.sub.2 and
R.sub.3 are as described for Structural Formulas (I) or (VI). Q in
Structural Formulas (VII) and (VIII) is preferably a covalent
bond.
[0048] Yet another embodiment of the present invention is one of
the novel compounds described herein, wherein the compound is
radioactively labeled, i.e., comprises a radioactive isotope (e.g.,
.sup.3H or .sup.14C) at a specific site in the compound at level
significantly greater than the natural abundance of the isotope.
"Significantly greater than natural abundance" means that the
amount of isotope greater than natural abundance can be assessed by
suitable means (e.g., scintillation counting). Radiolabeled,
preferably tritiated, (S)-3-{4-[3-(Biphenyl-4-yl-
oxy)-propoxy]-phenyl}-2-methoxy-propionic acid is one example of a
radiolabeled compound of the invention. Radiolabeled compounds, can
be advantageously used to assess binding of test compound to
PPAR.gamma..
[0049] Yet another embodiment of the present invention is a method
for determining whether a compound does or does not interact
directly (e.g., binds) with PPAR.gamma.. The method comprises the
step of specifically binding a radioactively labeled compound
described herein to the ligand binding domain of a PPAR.gamma.
receptor. The receptor is then combined with a test compound and
the amount of specific binding of the radioactively labeled
compound is assessed. Any decrease in the binding of the
radiolabeled compound indicates that the test compound interacts
directly with the peroxisome proliferator-activated receptor.
[0050] The compounds of the present invention and pharmaceutically
acceptable salts, solvates and hydrates, stereoisomers thereof
lower one or more of the following in mammals: glucose, insulin,
triglycerides, fatty acids and/or cholesterol. They are therefore
believed to be effective in treating hyperglycemia, dyslipidemia,
Type II diabetes, Type I diabetes, hypertriglyceridemia, syndrome X
insulin resistance, heart failure, diabetic dyslipidemia,
hyperlipidemia, hypercholesteremia, hypertension, obesity, anorexia
bulimia, polycystic ovarian syndrome, anorexia nervosa,
cardiovascular disease or other diseases where insulin resistance
is a component or other disorders modulated by a peroxisome
proliferator activated receptor.
DETAILED DESCRIPTION OF THE INVENTION
[0051] In the Schemes, Preparations and Examples below, various
reagent symbols and abbreviations have the following meanings:
[0052] BINAP 2,2'-Bis(diphenylphosphino)-1,1'-binaphthyl
[0053] Boc t-butoxycarbonyl
[0054] CBZ benzyloxycarbonyl
[0055] DCM dichloromethane
[0056] DEAD diethyl azodicarboxylate
[0057] DIAD diisopropyl azodicarboxylate
[0058] DIPEA diisopropylethylamine
[0059] DMAP 4-dimethylamino pyridine
[0060] DMF N,N-dimethylformamide
[0061] DMSO dimethylsulfoxide
[0062] eq. equivalent(s)
[0063] EDC 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide HCl
[0064] ESI-MS electron spray ion-mass spectroscopy
[0065] Et ethyl
[0066] EtOAc ethyl acetate
[0067] FMOC 9-Flurorenylmethyl carbamate
[0068] HATU O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium
hexafluorophosphate
[0069] HOAT: 1-hydroxy-7-azabenzotriazole
[0070] HOBT 1-hydroxybenzotriazole hydrate
[0071] HPLC high performance liquid chromatography
[0072] HRMS high resolution mass
[0073] LRMS low resolution mass
[0074] Me methyl
[0075] Ms methanesulfonyl.
[0076] Pd.sub.2(dba).sub.3
tris(dibenzylideneacetone)dipalladium(0)
[0077] Ph phenyl
[0078] Phe phenylalanine
[0079] Pr propyl
[0080] r.t. room temperature
[0081] TBAF tetrabutylammonium fluoride
[0082] TBS tert-butyldimethylsilyl
[0083] TFA trifluoroacetic acid
[0084] TEA triethylamine
[0085] THF tetrahydrofuran
[0086] Tic 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid
[0087] TLC thin-layer chromatography
[0088] In one preferred embodiment, the compound of the present
invention is represented by Structural Formula (IX): 6
[0089] Ar, Phenyl Ring A and R.sub.1 in Structural Formula (IX) are
as defined in Structural Formulas (I) or (VI). R.sub.1 is
preferably para to W.sub.1 and is represented by Structural Formula
(II), more preferably Structural Formulas (III) or (IV) and even
more preferably, Structural Formula (V).
[0090] p is an integer from one to nine, preferably one to
four.
[0091] W.sub.1 is --O--, --C(O), --OCH.sub.2--, --CH.sub.2--,
--NR.sub.8--, --NR.sub.8CO--, --NR.sub.8CH--, --C(.dbd.NOH)-- or
--CH(NR.sub.7R.sub.8)--.
[0092] R.sub.7 and R.sub.8 are independently --H, an aliphatic
group, a substituted aliphatic group, an aromatic group or a
substituted aromatic group.
[0093] In a more preferred embodiment, the compound of the present
invention is represented by a structural formula selected from
Structural Formulas (X)-(XVIII): 78
[0094] Ar, Phenyl Ring A, R.sub.2 and R.sub.3 in Structural
Formulas (X)-(XIX) are as described for Structural Formula (IX).
Preferably, R.sub.2 and R.sub.3 are as described for Structural
Formula (II). More preferably, --CH.sub.2CH(OR.sub.2)COOR.sub.3 in
Structural Formulas (X)-(XIX) is represented by Structural Formulas
(III) or (IV) and even more preferably by Structural Formula
(V).
[0095] In another preferred embodiment the compound of the present
invention is represented by Structural Formula (XX): 9
[0096] Ar and Phenyl Ring A in Structural Formula (XX) are as
described for Structural Formulas (I) or (VI) and t is an integer
from 1 to about 5.
[0097] In a more preferred embodiment, R.sub.1 in structural
Formula (XX) is para to the carbon bonded to the alkyne group and
is represented by Structural Formula (II), more preferably by
Structural Formulas (III) or (IV) and even more preferably by
Structural Formula (V). Preferably, t is 1, 2 or 3.
[0098] In another preferred embodiment, the compound of the present
invention is represented by Structural Formula (XXI): 10
[0099] Ar and Phenyl Ring A in Structural Formula (XXI) are as
described for Structural Formulas (I) or (VI).
[0100] p is zero, one or two.
[0101] W.sub.2 is --O--, --C(O)--, --OCH.sub.2--, --CH.sub.2--,
--NR.sub.8--, --NR.sub.8CO--, --NR.sub.8CH--, --C(.dbd.NOH)-- or
--CH(NR.sub.7R.sub.8)--. W.sub.2 is preferably --O--.
[0102] R.sub.7 and R.sub.8 are independently --H, an aliphatic
group, a substituted aliphatic group, an aromatic group or a
substituted aromatic group.
[0103] R.sub.11 and R.sub.12 are independently a C1-C6 alkyl group
(preferably C1-C3 alkyl group), or, taken together are a
substituted or unsubstituted ethylene, propylene or butylene
group.
[0104] In a more preferred embodiment, the compound of the present
invention is represented by a structural formula selected from
Structural Formulas (XXII)-(XXVI): 11
[0105] Ar and Phenyl Ring A in Structural Formulas (XXII)-(XXVI)
are as described for Structural Formula (XXI) and R.sub.2 and
R.sub.3 in Structural Formulas (XXII)-(XXVI) are as described in
Structural Formula (II). In Structural Formula (XXVI), W.sub.3 is a
covalent bond, methylene or ethylene and R.sub.13 and R.sub.14 are
methyl, ethyl or propyl and are the same or different, preferably
the same. Preferably, --CH.sub.2CH(OR.sub.2)COOR.sub.3 in
Structural Formulas (XXII)-(XXVI) is represented by Structural
Formulas (III) or (IV), more preferably by Structural Formula
(V).
[0106] In another preferred embodiment the compound of the present
invention is represented by Structural Formula (XXVII): 12
[0107] Ar, Phenyl Ring A, R.sub.2 and R.sub.3 in Structural
Formulas (XXVII) are as described for Structural Formulas (I) or
(VI); W.sub.4 and W.sub.5 are independently methylene or ethylene;
and R.sub.15 is --H and R.sub.16 is a C1-C6 alkyl group (preferably
methyl ethyl or propyl), or R.sub.15 and R.sub.16, taken together,
are .dbd.O or .dbd.CH.sub.2. Preferably,
--CH.sub.2CH(OR.sub.2)COOR.sub.3 in Structural Formula (XXVII) is
represented by Structural Formulas (III) or (IV), more preferably
by Structural Formula (V).
[0108] An "aliphatic group" is non-aromatic, consists solely of
carbon and hydrogen and may optionally contain one or more units of
unsaturation, e.g., double and/or triple bonds. An aliphatic group
may be straight chained, branched or cyclic. When straight chained
or branched, an aliphatic group typically contains between about 1
and about 10 carbon atoms, more typically between about 1 and about
6 carbon atoms. When cyclic, an aliphatic group typically contains
between about 3 and about 10 carbon atoms, more typically between
about 3 and about 7 carbon atoms. Aliphatic groups are preferably
C1-C10 straight chained or branched alkyl groups (i.e., completely
saturated aliphatic groups), more preferably C1-C6 straight chained
or branched alkyl groups. Examples include methyl, ethyl, n-propyl,
iso-propyl, n-butyl, sec-butyl and tert-butyl.
[0109] A "haloaliphatic group" is an aliphatic group, as defined
above, substituted with one or more halogen atoms.
[0110] A "haloalkyl group" is an alkyl group (i.e., a saturated
aliphatic group), as defined above, substituted with one or more
halogen atoms. Examples included --CF.sub.3, --CHF.sub.2,
--CH.sub.2F, --CF.sub.2CF.sub.3 and the like.
[0111] An "aralkyl group" is an alkyl group substituted with an
aromatic group, preferably a phenyl group. A preferred aralkyl
group is a benzyl group. Suitable aromatic groups are described
below and suitable alkyl groups are described above. Suitable
substituents for an aralkyl group are described below.
[0112] An "aralkenyl group" is an alkenyl group substituted with an
aromatic group. An "alkenyl group" is an aliphatic group with one
or more carbon carbon double bonds. Suitable aromatic groups are
described below. Suitable aliphatic groups are defined above.
Suitable substituents for an aralkenyl group are described
below.
[0113] An "alkyl group" has the formula --CH.sub.2CH.dbd.CH.sub.2.
Suitable substituents for an alkyl group are described below
[0114] An "alkylene group" is a polymethylene group, i.e.,
--(CH.sub.2).sub.n--, wherein n is a positive integer. Preferably,
n is an integer from about 2 to about 10, more preferably from
about 2 to about 7. A "substituted alkylene group" is an alkylene
group in which one or more methylene hydrogen atoms are replaced
with a substituent. Suitable substituents are described below.
[0115] An "arylene" is an aromatic group in which at least two
carbon atoms are bonded to moieties other than hydrogen. Suitable
arylene groups are those corresponding to the aromatic groups
described herein.
[0116] A "sulfonamide group" is represented by
--S(O).sub.2NH.sub.2. A "substituted sulfonamide group" is
represented by --S(O).sub.2N(R).sub.2, wherein each R is
independently --H, C1-C6 alkyl, C1-C6 haloalkyl or aryl-C0-C4-alkyl
and at least one R is not --H.
[0117] An "acylsulfonamide group" is represented by
--S(O).sub.2NH--C(O)--R wherein R is --H or a C1-C6 alkyl group or
a C1-C6 haloalkyl group. A "substituted acylsulfonamide group" is
represented by --S(O).sub.2NR'--C(O)R, wherein R is --H or a C1-C6
alkyl group or C1-C6 haloalkyl group and R' is C1-C6 alkyl, C1-C6
haloalkyl or aryl-C0-C4-alkyl.
[0118] The term "heteroalkylene group" refers to an alkylene group
in which one or more methylene groups have been replaced by a
functional group, e.g., --(CH.sub.2).sub.p-Z-(CH.sub.2).sub.q--
wherein p is a positive integer and q is zero or a positive integer
such that p+q is less than 10 and Z is a functional group. Examples
of suitable functional groups include --CH.dbd.CH--, --C.ident.C--,
--O--, --CO--, --NR.sub.8--, --NR.sub.8CO--, --C(.dbd.NOH)--,
--S(O).sub.k-- and --CH(NR.sub.7R.sub.8)-- wherein each R.sub.7 and
each R.sub.8 is independently --H, an aliphatic group, a
substituted aliphatic group, an aromatic group or a substituted
aromatic group; and k is 0, 1 or 2. Preferably, a heteroalkylene
group is between about 2 and 10 atoms in length. For purposes of
determining the length of a heteroalkylene group, in this
application a functional group is considered to be one atom. Thus,
for example, --(CH.sub.2).sub.3--CO--NH(CH.sub.2).sub.2-- is six
atoms in length (five methylene carbons and a functional group);
and CH.sub.2).sub.3--C(.dbd.NOH)--(CH.sub.2).sub.2-- is also six
atoms in length (five methylene carbons and an oxime carbon).
Examples of preferred heteroalkylene groups include
--(CH.sub.2).sub.2--O--, --(CH.sub.2).sub.3--O--,
--(CH.sub.2).sub.4--O--, --CH.sub.2--C.ident.CH-- -,
--(CH.sub.2).sub.2--C.ident.CH--, --(CH.sub.2).sub.3--C.ident.CH--,
--(CH.sub.2).sub.4--C.ident.CH--, --(CH.sub.2).sub.5--C.ident.CH--,
--(CH.sub.2)CO--, --(CH.sub.2).sub.2CO--, --(CH.sub.2).sub.3CO--,
--(CH.sub.2).sub.4CO--, --(CH.sub.2).sub.2--C(.dbd.NOH)--,
--(CH.sub.2).sub.3--C(.dbd.NOH)--, --(CH.sub.2).sub.4(.dbd.NOH)--,
--(CH.sub.2).sub.2--NR.sub.8--, --(CH.sub.2).sub.3--NR.sub.8--,
--(CH.sub.2).sub.4--NR.sub.8--, --(CH.sub.2).sub.2--NR.sub.8CO--,
--(CH.sub.2).sub.3--NR.sub.8CO--, --(CH.sub.2).sub.4--NR.sub.8CO--,
--(CH.sub.2).sub.2--OCH.sub.2--, --(CH.sub.2).sub.3--OCH.sub.2--,
--(CH.sub.2).sub.4--OCH.sub.2--,
--(CH.sub.2).sub.2--NR.sub.8CH.sub.2--,
--(CH.sub.2).sub.3--NR.sub.8CH.sub.2--,
--(CH.sub.2).sub.4--NR.sub.8CH.su- b.2--,
--(CH.sub.2).sub.2CH(NR.sub.7R.sub.8)--,
--(CH.sub.2).sub.3CH(NR.su- b.7R.sub.8)-- and
--(CH.sub.2).sub.4--CH(NR.sub.7R.sub.8)--.
[0119] A "substituted heteroalkylene group" is a heteroalkylene
group in which one or more methylene hydrogen atoms are replaced
with a substituent. Preferred substituents include .dbd.O,
.dbd.CH.sub.2, C1-C6 alkyl and C2-C4 alkylene. When a
heteroalkylene group is substituted with a C2-C4 alkylene group,
the C2-C4 alkylene group together with the carbon atoms of the
heteroalkylene group to which the two ends of the C2-C4 alkylene
group are bonded and any intervening carbon atoms form a cycloalkyl
ring. Structural Formula (XX) provides an example of a
heteroalkylene group substituted with a C2-C4 alkylene group, which
is represented by R.sub.11 and R.sub.12 taken together.
Specifically, R.sub.11 and R.sub.12, taken together with
--CH--(CH.sub.2).sub.pCH-- can form a cycloalkyl ring. Other
examples of heteroalkylene groups substituted by an alkylene are
shown in the following structural formulas: 13
[0120] Other suitable substituents for a heteroalkylene group are
described below.
[0121] A "nonaromatic heterocyclic ring" (or also referred to as a
"heterocyclic ring") is a monocyclic, bicyclic, or tricyclic
nonaromatic ring of 3 to 14 ring atoms which are saturated or
partially saturated containing carbon and from one to four
heteroatoms selected from N, O or S. The term "nonaromatic
heterocyclic ring" includes nitrogen-containing heterocyclic rings,
which contains from one to three nitrogen atoms and optionally
further contains one other heteroatom selected from O or S.
Examples include morpholinyl, thiomorphonlyl, pyrrolindinyl,
pierazinyl, piperidinyl, azetidinyl, azacycloheptyl, or
N-phenylpiperazinyl. The tern "non-aromatic heterocyclic ring" also
includes non-aromatic heterocyclic rings fused to aromatic group,
e.g., 1,3-benzodioxole, 4-chromanone, and phthalimide. A
"non-aromatic heterocyclic ring" may be optionally substituted with
a designated number of substituents, as described below.
[0122] An "aromatic group" (also referred to as an "aryl group") as
used herein includes carbocyclic aromatic groups, heterocyclic
aromatic groups (also referred to as "heteroaryl") and fused
polycyclic aromatic ring system as defined herein.
[0123] A "carbocyclic aromatic group" is an aromatic ring of 5 to
14 carbons atoms, and includes a carbocyclic aromatic group fused
with a 5-or 6-membered cycloalkyl group such as indan. Examples of
carbocyclic aromatic groups include, but are not limited to,
phenyl, 1-naphthyl, 2-naphyl, 1-anthracenyl 2-anthracenyl,
phenanthrenyl, fluorene, 9-fluorenone, indan and the like. A
carbocyclic aromatic group is optionally substituted with a
designated number of substituents, described below for aromatic
groups.
[0124] A "heterocyclic aromatic group" (or "heteroaryl") is a
monocyclic, bicyclic or tricyclic aromatic ring of 5- to 14-ring
atoms of carbon and from one to four heteroatoms selected from O,
N, or S. Examples of heteroaryl include, but are not limited to
N-imidazolyl, 2-imidazole, 2-thienyl, 3-thienyl, 2-furanyl,
3-furanyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl,
4-pyrimidyl 2-pyranyl, 3-pyranyl, 4-pyrazolyl, 5-pyrazolyl,
2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-oxazoyl, 4-oxazoyl,
5-oxazoyl, 2-imidazolyl, isoxazoyl, pyrrolyl, pyrazinyl, and
purinyl and the like. Heterocyclic aromatic (or heteroaryl) as
defined above may be optionally substituted with a designated
number of substituents, as described below for aromatic groups.
[0125] A "fused polycyclic aromatic" ring system is a carbocyclic
aromatic group or heteroaryl fused with one or more other
heteroaryl or nonaromatic heterocyclic ring. Examples include
2,3-dihydrobenzofuran, dibenzothiophene, dibenzofuran,
2-benzothienyl, 3-benzothienyl, 2-benzofuranyl, 3-benzofuranyl,
2-indolyl, 3-indolyl, 2-quinolinyl, 3-quinolinyl, 2-benzothiazolyl,
2-benzooxazolyl, 2-benzoimidazolyl, 2-qinolinyl, 3-quinolinyl,
1-isoqinolinyl, 3-quinolinyl, 1-isoinoldyl, 3-isoindolyl,
benzotriazolyl and the like. Fused polycyclic aromatic ring systems
may optionally be substituted with a designated number of
substituents, as described below for aromatic groups.
[0126] "Halo" refers to fluoro, chloro, bromo and iodo.
[0127] Preferred examples of suitable values for Ar in Structural
Formulas (I), and (VI)-(XXVII) are shown below: 141516
[0128] Rings B-Z are independently substituted or unsubstituted.
Other examples of suitable groups for Ar include substituted or
unsubstituted benzoylnaphthyl, thienylphenyl and naphthoylphenyl.
Still other examples of suitable values for Ar are found in
Examples 1-379. These aromatic groups, when used as values for Ar,
can be substituted or unsubstituted, as shown in Examples 1-379,
or, alternatively, can is contain one or more other aromatic group
substituents that are described herein.
[0129] X is --O--, --S--, --CH.sub.2-- or --C(O).
[0130] Z is a covalent bond, --O--, (--CH.sub.2).sub.q--,
--CH(CH.sub.3)(CH.sub.2).sub.q--,
--C(CH.sub.3).sub.2(CH.sub.2).sub.q--,
--(CH.sub.2).sub.qCH(CH.sub.3)--,
--(CH.sub.2).sub.qC(CH.sub.3).sub.2--, --O(CH.sub.2).sub.q--,
--(CH.sub.2).sub.qO--, --(CH.sub.2).sub.qNH--,
--(CH.sub.2).sub.qNH--, --(CH.sub.2).sub.qCHR.sub.20--,
--CHR.sub.20(CH.sub.2).sub.q--,
--(CH.sub.2).sub.qCR.sub.20R.sub.20--,
--(CH.sub.2).sub.qCR.sub.20R.sub.20--,
--(CH.sub.2).sub.qNR.sub.20--, --NR.sub.20(CH.sub.2).sub.q--,
--(CH.sub.2).sub.qC(.dbd.NOH)--, --C(.dbd.NOH)(CH.sub.2).sub.q--,
--CH(OH)--(CH.sub.2).sub.q--, --(CH.sub.2).sub.q--CH(OH)--,
--CO--(CH.sub.2q--, --(CH.sub.2).sub.q--CO-- -,
--COO--(CH.sub.2).sub.q--, --OCO--(CH.sub.2).sub.q--,
--(CH.sub.2).sub.q--OCO--, --(CH.sub.2).sub.q--COO--,
--(CH.sub.2).sub.qCO--NH--, --(CH.sub.2).sub.qNH--CO--,
--(CH.sub.2).sub.qCONR.sub.20--, --CONR.sub.20(CH.sub.2).sub.q--,
--(CH.sub.2).sub.qNR.sub.20CO-- or --NR.sub.20CO(CH.sub.2).sub.q--.
Z is preferably a covalent bond, --C(.dbd.NOH), --O-- or --C(O)--
(more preferably --O-- or --C(O)--); and q is 0, 1, 2 or 3,
preferably 0 or 1.
[0131] Each R.sub.20 is independently a C1-C5 alkyl group or
halogenated C1-C5 alkyl group.
[0132] Especially preferred values groups for Ar in Structural
Formulas (I) and (VI)-(XXVII) are shown below: 17
[0133] Phenyl Rings A' and A" are substituted or unsubstituted.
[0134] Suitable substituents for an aromatic group, including the
aromatic group represented by Ar (e.g., Phenyl Rings A' and A" and
Rings B-Z) and Phenyl Ring A, an aliphatic group, an alkyl group,
an alkylene group, a heteroalkylene group, a non-aromatic
heterocyclic group, an aralkyl group, an aralkenyl group and an
alkyl group are those which do not significantly diminish the
activity of the compound at the Peroxisome Proliferator Activated
Receptors (PPARs), e.g., decrease the activity by more than a
factor of five (preferably no more than a factor of two) compared
with the corresponding compound without the substituent Examples of
substituents include halogen (--Br, --Cl, --I and --F)--R, --OR,
--CN, --NO.sub.2, --N(R).sub.2, --COR, --COOR, --CON(R).sub.2,
--SO.sub.kR (k is 0, 1 or 2) and --NH--C(.dbd.NH)--NH.sub.2. Other
examples include sulfonamide, acylsulfonamide, --NR--CO--R,
--OS(O)R, --OS(O).sub.2R, cycloalkyl groups, substituted or
unsubstituted non-aromatic heterocyclic groups,
O(CH.sub.2).sub.rCOOH --O--O(CH.sub.2).sub.r--N(R).sub.2,
--O(CH.sub.2).sub.r-(cycloalkyl), --O(CH.sub.2).sub.rOH,
--O(CH.sub.2).sub.r--OSi(R).sub.3, and
--(CH.sub.2).sub.aCH(OR.sub.30)(CH- .sub.2).sub.bCOOR.sub.31. Each
R is independently --H, an aliphatic group, a substituted aliphatic
group, a halogenated aliphatic group, a benzyl group, a substituted
benzyl group, an aromatic group or a substituted aromatic group,
and preferably --H, an alkyl group (e.g., a C1-C10 alkyl group), a
halogenated alkyl group (e.g., a C1-C.sub.10 halogenated alkyl
group), a phenyl group or a substituted phenyl group; R.sub.30 is a
C1-C6 alkyl group or C1-C6 halogenated alkyl group, R.sub.31 is
--H, a C1-C6 alkyl group or C1-C6 halogenated alkyl group; r is an
integer from 1 to 6; a and b are independently 0, 1 or 2. An
aromatic group, benzylic group, an aliphatic group, an alkyl group,
an alkylene group, a heteroalkylene group, a non-aromatic
heterocyclic group, aralkyl group and aralkenyl group can have more
than one substituent. Other examples of suitable substituents for
an aromatic group represented by Ar are those found at the
corresponding position of the compounds descried in the
Exemplification Section.
[0135] Preferred substituents for Rings B-Z include halogen,
--R.sub.9, --OR.sub.9, --COR.sub.9, --COOR.sub.9, --CN, a
non-aromatic heterocyclic group, an allylic group,
--(CH.sub.2).sub.aCH(OR.sub.30)(CH.sub.2).sub.bC- OOR.sub.3, or
--NR.sub.9C(O)R.sub.9, R.sub.9 is --H, an alkyl group (e.g., a
C1-C10 alkyl group), cycloalkyl, a halogenated alkyl group (e.g., a
C1-C10 halogenated alkyl group) or an aromatic group. R.sub.30,
R.sub.31, a and b are as described above; preferably R.sub.30 is
methyl or ethyl, R.sub.31 is --H.sub.3 and a and b are one.
[0136] More preferably, suitable substituents for Rings B-Z include
one or more groups selected from halogen, C1-C8 straight chained or
branched alkyl, C1-C8 straight chained or branched halogenated
alkyl (e.g., --CF.sub.3), C3-C8 cycloalkyl, C1-C8 straight chained
or branched alkanoyl, C1-C8 straight chained or branched alkoxy
(e.g., methoxy), --Br, --F, N-morpholino, --COOH, --OH, --CN, or
C1-C8 straight chained or branched halogenated alkoxy (e.g.,
--OCF.sub.3).
[0137] Suitable substituents for Phenyl Rings A' and A" are as
described above for Rings B-Z.
[0138] Preferred substituents for Phenyl Ring A include halogen,
--OR.sub.10, --R.sub.10, aromatic group, substituted aromatic
group, aralkyl, substituted aralkyl, aralkenyl, substituted
aralkenyl, alkyl and substituted alkyl and R.sub.10 is --H, an
alkyl group (e.g., a C1-C10 all group) or a halogenated alkyl group
(e.g., a C1-C10 halogenated alkyl group). Specific examples of
suitable substituents for Phenyl Ring A include --F, --Cl,
--OCH.sub.3, --OCF.sub.3, --CH.sub.3, ethyl, n-propyl, iso-propyl,
alkyl, 2-phenylethenyl, 2-phenylethyl, phenyl, -o-biphenyl,
-m-biphenyl, -p-biphenyl, -o-C.sub.6H.sub.40CH.sub.3,
-m-C.sub.6H.sub.4OCH.sub.3, -p-C6H.sub.4OCH.sub.3,
-o-C.sub.6H.sub.4F, -m-C.sub.6H.sub.4F and -p-C.sub.6H.sub.4F.
[0139] Another embodiment of the present invention is a compound
represented by Structural Formula (XLII): 18
[0140] Ar and R.sub.1 in Structural Formula (XLI) are as defined
above in Structural Formulas (I) and (VI); s is 0, 1 or 2; Ar.sub.1
is a substituted or unsubstituted arylene group; W.sub.6 is a
covalent bond, --W.sub.1--, --CH.sub.2W.sub.1-- or
--W.sub.1CH.sub.2--; W.sub.7 is a covalent bond or --CH.sub.2-- and
W.sub.1 is as defined above. Preferably R.sub.1 is represented by
Structural Formula (II), s is 0 or 1, Ar.sub.1 is phenylene (ortho,
meta or para substituted), W.sub.7 is a covalent bond and W.sub.1
is --O--. More preferably, Ar is represented by any one of
Structural Formulas (XXVIII)-(XXXIX) and R.sub.1 is represented by
Structural Formulas (III) or (IV). Even more preferably, Ar is
represented by Structural Formulas (XL) or (XLI) and R.sub.1 is
represented by Structural Formula (V).
[0141] Also included in the present invention are methods of
treatment as described above, wherein the compound represented by
Structural Formula (XLI) is administered as the therapeutic agent
and the use of the compound for the manufacture of a medicament for
the treatment of the PPAR mediated disorders described herein.
[0142] The following are specific examples of the compounds of the
present invention:
[0143]
(2S)-3-{4-[3-(Biphenyl-4-yloxy)-prop-1-ynyl]-phenyl}-2-methoxy-prop-
ionic acid (Compound 1);
[0144]
(2S)-3-{4-[3-(4-Benzoyl-phenoxy)-prop-1-ynyl]-phenyl}-2-methoxy-pro-
pionic acid (Compound 2);
[0145]
(2S)-2-Methoxy-3-{4-[3-phenoxy-phenoxy)-prop-1-ynyl]-phenyl}-propio-
nic acid (Compound 3);
[0146]
(2S)-3-{4-[3-(4-Fluoro-phenoxy)-prop-1-ynyl]-phenyl}-2-methoxy-prop-
ionic acid (Compound 4);
[0147]
(2S)-2-Methoxy-3-{4-[3-(3-phenyl-benzofuran-6-yloxy)-prop-1-ynyl]-p-
henyl}-propionic acid (Compound 5);
[0148]
(2S)-3-{4-[3-(4-Butyl-phenoxy)-prop-1-ynyl]-phenyl}-2-methoxy-propi-
onic acid (Compound 6);
[0149]
(2S)-2-Methoxy-3-(4-{3-[4-(4-trifluoromethyl-phenoxy)-phenoxy]-prop-
-1-ynyl}-phenyl)-propionic acid (Compound 7);
[0150]
(2S)-2-Methoxy-3-{4-[3-(9-oxo-9H-fluoren-2-yloxy)-prop-1-ynyl]-phen-
yl}-propionic acid (Compound 8);
[0151]
(2S)-2-Methoxy-3-{4-[3-(4-oxo-2-phenyl-4H-chromen-7-yloxy)-prop-1-y-
nyl]-phenyl}-propionic acid (Compound 9);
[0152]
(2S)-3-(4-{3-[4-(2-Fluoro-benzoyl)-phenoxy]-prop-1-ynyl}-phenyl)-2--
methoxy-propionic acid (Compound 10);
[0153]
(2S)-2-Methoxy-3-{4-[3-(3-phenylamino-phenoxy)-prop-1-ynyl]-phenyl}-
-propionic acid (Compound 11);
[0154]
(2S)-3-({3-[4-(4-Fluoro-benzoyl)-phenoxy]-prop-1-ynyl}-phenyl)-2-me-
thoxy-propionic acid (Compound 12);
[0155]
(2S)-2-Methoxy-3-{4-[3-(4-oxo-2-phenyl-4H-chromen-6-yloxy)-prop-1-y-
nyl]-phenyl}-propionic acid (Compound 13);
[0156]
(2S)-3-(4-{3-[3-(4-Fluoro-phenyl)-benzofuran-6-yloxy]-prop-1-ynyl}--
phenyl)-2-methoxy-propionic acid (Compound 14);
[0157]
(2S)-2-Methoxy-3-(4-{3-[4-(1-methyl-1-phenyl-ethyl)-phenoxy]-prop-1-
-ynyl}-phenyl)-propionic acid (Compound 15);
[0158]
(2S)-2-Methoxy-3-{4-[3-(4-phenylacetyl-phenoxy)-prop-1-ynyl]-phenyl-
}-propionic acid (Compound 16);
[0159]
(2S)-3-{4-[3-(4-Benzyl-phenoxy)-prop-1-ynyl]-phenyl}-2-methoxy-prop-
ionic acid (Compound 17);
[0160]
(2S)-3-[4-(3-{4-[(2-Fluoro-phenyl)-hydroxyimino-methyl]-phenoxy}-pr-
op-1-ynyl)-phenyl]-2-methoxy-propionic acid (Compound 18);
[0161]
(2S)-3-(4-{3-[4-(Hydroxyimino-phenyl-methyl)-phenoxy]-prop-1-ynyl}--
phenyl)-2-methoxy-propionic acid (Compound 19);
[0162]
(2S)-3-[4-(3-{4-[(4-Fluoro-phenyl)-hydroxyimino-methyl]-phenoxy}-pr-
op-1-ynyl)-phenyl]-2-methoxy-propionic acid (Compound 20);
[0163]
(2S)-3-{4-[5-(Biphenyl-4-yloxy)-pent-1-ynyl]-phenyl}-2-methoxy-prop-
ionic acid (Compound 21);
[0164]
(2S)-2-Methoxy-3-{4-[5-(4-phenoxy-phenoxy)-pent-1-ynyl]-phenyl}-pro-
pionic acid (Compound 22),
[0165]
(2S)-3-{4-[5-(4-Benzoyl-phenoxy)-pent-1-ynyl]-phenyl}-2-methoxy-pro-
pionic acid (Compound 23);
[0166]
(2S)-3-{4-[5-(4-Benzyl-phenoxy)-pent-1-ynyl]-phenyl}-2-methoxy-prop-
ionic acid (Compound 24);
[0167]
(2S)-3-(4-{5-[4-(4-Fluoro-benzoyl)-phenoxy]-pent-1-ynyl}-phenyl)-2--
methoxy-propionic acid (Compound 25);
[0168]
(2S)-2-Methoxy-3-(4-{5-[4-(4-trifluoromethyl-phenoxy)-phenoxy]-pent-
-1-ynyl}-phenyl)-propionic acid (Compound 26);
[0169]
(2S)-2-Methoxy-3-{4-[5-(4-oxo-2-phenyl-4H-chromen-7-yloxy)-pent-1-y-
nyl]-phenyl}-propionic acid (Compound 27);
[0170]
(2S)-2-Methoxy-3-{4-[5-(4-oxo-2-phenyl-4H-chromen-6-yloxy)-pent-1-y-
nyl]-phenyl}-propionic acid (Compound 28);
[0171]
(2S)-2-Methoxy-3-(4-{5-[4-(1-methyl-1-phenyl-ethyl)-phenoxy]-pent-1-
-ynyl}-phenyl)-propionic acid (Compound 29);
[0172]
(2S)-2-Methoxy-3-{4-[5-(9-oxo-9H-fluoren-2-yloxy)-pent-1-ynyl]-phen-
yl}-propionic acid (Compound 30);
[0173]
(2S)-2-Methoxy-3-{4-[5-3-phenylamino-phenoxy)-pent-1-ynyl]-phenyl}--
propionic acid (Compound 31);
[0174]
(2S)-3-(4-{5-[4-(2-Fluoro-benzoyl)-phenoxy]-pent-1-ynyl}-phenyl)-2--
methoxy-propionic acid (Compound 32);
[0175]
(2S)-2-Methoxy-3-{4-[5-(3-phenyl-benzofuran-6-yloxy)-pent-1-ynyl]-p-
henyl}-propionic acid (Compound 33);
[0176]
(2S)-3-(4-{5-[3-(4-Fluoro-phenyl)-benzofuran-6-yloxy]-pent-1-ynyl}--
phenyl)-2-methoxy-propionic acid (Compound 34);
[0177]
(2S)-2-Methoxy-3-{4-[5-(4-phenylacetyl-phenoxy)-pent-1-ynyl]-phenyl-
}-propionic acid (Compound 35);
[0178]
(2S)-3-{4-[5-(4-Butyl-phenoxy)-pent-1-ynyl]-phenyl}-2-methoxy-propi-
onic acid (Compound 36);
[0179]
(2S)-3-[4-(5-{4-[(2-Fluoro-phenyl)-hydroxyimino-methyl]-phenoxy}-pe-
nt-1-ynyl)-phenyl]-2-methoxy-propionic (Compound 37);
[0180]
(2S)-3-[4-(5-{4-[(4-Fluoro-Phenyl)-hydroxyimino-methyl]-phenoxy}-pe-
nt-1-ynyl)-phenyl]-2-methoxy-propionic acid (Compound 38);
[0181]
(2S)-3-(4-{5-[4-(Hydroxyimino-phenyl-methyl)-phenoxy]-pent-1-ynyl}--
phenyl)-2-methoxy-propionic acid (Compound 39);
[0182]
(2S)-3-{4-[4-(Biphenyl-4-yloxy)-but-1-ynyl]-phenyl}-2-methoxy-propi-
onic acid (Compound 40);
[0183]
(2S)-2-Methoxy-3-{4-[4-(4-phenoxy-phenoxy)-but-1-ynyl]-phenyl}-prop-
ionic acid (Compound 41);
[0184]
(2S)-3-{4-[4-(4-Benzoyl-phenoxy)-but-1-ynyl]-phenyl}-2-methoxy-prop-
ionic acid (Compound 42);
[0185]
(2S)-3-(4-{4-[4-(Hydroxyimino-phenyl-methyl)-phenoxy]-but-1-ynyl}-p-
henyl)-2-methoxy-propionic acid (Compound 43);
[0186]
(2S)-3-(4-{4-[4-Fluoro-benzoyl)-phenoxy]-but-1-ynyl}-phenyl)-2-meth-
oxy-propionic acid (Compound 44);
[0187]
(2S)-3-(4-{4-[3-(4-Fluoro-phenyl)-benzofuran-6-yloxy]-but-1-ynyl}-p-
henyl)-2-methoxy-propionic acid (Compound 45);
[0188]
(2S)-2-Methoxy-3-(4-{4-[4-(4-trifluoromethyl-phenoxy)-phenoxy]-but--
1-ynyl}-phenyl)-propionic acid (Compound 46);
[0189]
(2S)-2-Methoxy-3-{4-[4-(4-oxo-2-phenyl-4H-chromen-7-yloxy)-but-1-yn-
yl]-phenyl}-propionic acid (Compound 47);
[0190]
(2S)-2-Methoxy-3-{4-[4-(4-oxo-2-phenyl-4H-chromen-7-yloxy)-but-1-yn-
yl]-phenyl}-propionic acid (Compound 48);
[0191]
(2S)-2-Methoxy-3-{4-[6-(4-phenoxy-phenoxy)-hex-1-ynyl]-phenyl}-prop-
ionic acid (Compound 49);
[0192]
(2S)-3-{4-[6-(4-Benzoyl-phenoxy)-hex-1-ynyl]-phenyl}-2-methoxy
propionic acid (Compound 50);
[0193]
(2S)-3-{4-[6-(Biphenyl-4-yloxy)-hex-1-ynyl]-phenyl}-2-methoxy-propi-
onic acid (Compound 51);
[0194]
(2S)-3-{4-[5-(Biphenyl-4-yloxy)-pentanoyl]-phenyl}-2-methoxy-propio-
nic acid (Compound 52);
[0195]
(2S)-3-{4-[5-(4-Benzoyl-phenoxy)-pentanoyl]-phenyl}-2-methoxy-propi-
onic acid (Compound 53);
[0196]
(2S)-2-Methoxy-3-{4-[5-(4-phenoxy-phenoxy)-pentanoyl]-phenyl}-propi-
onic acid (Compound 54);
[0197]
3-{4-[4-(4-Benzoyl-phenoxy)-butyryl]-phenyl}-2-methoxy-propionic
acid (Compound 55);
[0198]
(2S)-2-Methoxy-3-{4-[4-(4-phenoxy-phenoxy)-butyryl]-phenyl}-propion-
ic acid (Compound 56);
[0199]
(2S)-3-[4-(Biphenyl-4-yloxy)-butyryl-phenyl]-2-methoxy-propionic
acid (Compound 57);
[0200]
(2S)-3-{4-[6-(Biphenyl-4-yloxy)-hexanoyl]-phenyl}-2-methoxy-propion-
ic acid (Compound 58);
[0201]
(2S)-2-Methoxy-3-{4-[6-(4-phenoxy-phenoxy)-hexanoyl]-phenyl}-propio-
nic acid (Compound 59);
[0202]
(2S)-3-{4-[6-(4-Benzoyl-phenoxy)-hexanoyl]-phenyl}-2-methoxy-propio-
nic acid (Compound 60);
[0203]
(2S)-3-{4-[5-(Biphenyl-4-yloxy)-1-hydroxyimino-pentyl]-phenyl}-2-me-
thoxy-propionic acid (Compound 61);
[0204]
(2S,1'R*,2'S*)-3-(4-{2'-[4-(4-Fluoro-benzoyl)-phenoxy]-cyclopentylo-
xy}-phenyl)-2-methoxy-propionic acid (Compound 62);
[0205]
(2S)-(1'R,3'R)-2-Methoxy-3-{4-[1',3'-dimethyl-3-(4-phenoxy-phenoxy)-
-propoxyl]-phenyl}-propionic acid (Compound 63);
[0206]
(2S)-(1'R,3'R)-3-{4-[3-(4-Benzoylphenoxy)-1',3'-dimethylpropoxyl]-p-
henyl}2-methoxy-propionic acid (Compound 64);
[0207]
(2S)-(1'S,3'S)-2-Methoxy-3-{4-[1',3'-dimethyl-3-(4-phenoxy-phenoxy)-
-propoxyl]-phenyl}-propionic acid (Compound 65);
[0208]
(2S)-(1'S,3'S)-3-{4-[3-(4-Benzoylphenoxy)-1',3'-dimethylpropoxyl]-p-
henyl}2-methoxy-propionic acid (Compound 66);
[0209]
(2S)-(1'R,2'R)-2-Methoxy-3-{4-[1',2'-dimethyl-(4-phenoxy-phenoxy)-e-
thoxyl]-phenyl}-propionic acid (Compound 67);
[0210]
(2S)-(1'R,2'R)-3-{4-[1-(4-Benzoylphenoxy)-1',2'-dimethyl-ethoxyl]-p-
henyl}-2-methoxypropionic acid (Compound 68);
[0211]
(2S)-(1'S,4'S)-2-Methoxy-3-{4-[1'-methyl-4'-(4-phenoxy-phenoxy)-pen-
tyloxy]-phenyl}-propionic acid (Compound 69);
[0212]
(2S)-(1'S,4'S)-3-{4-[4-(4-Benzoyl-phenoxy)-1-methyl-pentyloxy]-phen-
yl}-2-methoxy-propionic acid (Compound 70);
[0213]
(2S)-(1'R,4'R)-2-Methoxy-3-{4-[1'-methyl-4'-(4-phenoxy-phenoxy)-pen-
tyloxy]-phenyl}-propionic acid (Compound 71);
[0214]
(2S)-(1'R,4'R)-3-{4-[4-(4-Benzoyl-phenoxy)-1-methyl-pentyloxy]-phen-
yl}-2-methoxy-propionic acid (Compound 72);
[0215]
(2S)-(1'S,2'S)-2-Methoxy-3-{4-[1',2'-dimethyl-(4-phenoxy-phenoxy)-e-
thoxyl]-phenyl}-propionic acid (Compound 73);
[0216]
(2S)-2-Methoxy-{4-[2-methylen-3-(4-phenoxy-phenoxy)-propoxyl]-pheny-
l}-propionic acid (Compound 74);
[0217]
(2S)-2-Methoxy-{4-[2-oxo-3-(4-phenoxy-phenoxy)-propoxyl]-phenyl}-pr-
opionic acid (Compound 75);
[0218]
(2S)-2-Methoxy-3-{4-[3-(4-phenoxy-phenoxymethyl)-benzyloxy]-phenyl}-
-propionic acid (Compound 76);
[0219]
(2S)-2-Methoxy-3-{4-[2-(4-phenoxy-phenoxymethyl)-benzyloxy]-phenyl}-
-propionic acid (Compound 77);
[0220]
(2S)-2-Methoxy-3-{4-[3-(4-phenoxy-phenoxy)-phenoxy]-phenyl}-propion-
ic acid (Compound 78),
[0221]
(2S)-3-[3'-(3-Benzoyl-phenoxymethyl)biphenyl-4-yl]-2-methoxy-propio-
nic acid (Compound 79);
[0222]
(2S)-3-[4'-(4-Benzoyl-phenoxymethyl)-biphenyl-4-yl-2-methoxy-propio-
nic acid (Compound 80);
[0223]
(2S)-(1'R*,3'R*)-3-{4-[3'-(Biphenyl-4-yloxy)-1'-cyclopentyloxy]-phe-
nyl}-2-methoxy-propionic acid (Compound 81);
[0224]
(2S)-(1'R*,3'S*)-3-{4-[3'-(Biphenyl-4-yloxy)-1'-cyclopentyloxy]-phe-
nyl}-2-methoxy-propionic acid (Compound 82);
[0225]
(2S)-(1'R*,3'R*)-2-Methoxy-3-{4-[3'-(4-phenoxy-phenoxy)-1'-cyclopen-
tyloxy]-phenyl}-propionic acid (Compound 83);
[0226]
(2S)-(1'R*,3'R*)-3-{4-[3-(4-Benzoyl-phenoxy)-cyclopentyloxy]-phenyl-
}-2-methoxy-propionic acid (Compound 84);
[0227]
(2S)-(1'R*,3'R*)-2-Methoxy-3-{4-[3-(4-phenylacetyl-phenoxy)-cyclope-
ntyloxy]-phenyl}-propionic acid (Compound 85);
[0228]
(2S)-(1'R,3'S)-3-{4-[3'-(Biphenyl-4-yloxy)-1'-cyclopentyloxy]-pheny-
l}-2-methoxy-propionic acid (Compound 86);
[0229]
(2S)-(1'S,3'R)-3-{4-[3'-(Biphenyl-4-yloxy)-1'-cyclopentyloxy]-pheny-
l}-2-methoxy-propionic acid (Compound 87);
[0230]
(2S)-(1'S,3'S)-3-{4-[3'-(Biphenyl-4-yloxy)-1'-cyclopentyloxy]-pheny-
l}-2-methoxy-propionic acid (Compound 88);
[0231]
(2S)-(1'R,3'R)-3-{4-[3'-(Biphenyl-4-yloxy)-1'-cyclopentyloxy]-pheny-
l}-2-methoxy-propionic acid (Compound 89);
[0232]
(2S)-(1'R,3's)-3-{4-[3'-(Biphenyl-4-yloxy)-1'-cyclohexyloxy]-phenyl-
}-2-methoxy-propionic acid (Compound 90);
[0233]
(2S)-(1'S,3'R)-3-{4-[3'-(Biphenyl-4-yloxy)-1'-cyclohexyloxy]-phenyl-
}-2-methoxy-propionic acid (Compound 91);
[0234]
(2S)-(1'R,3'R)-3-{4-[3'-(Biphenyl-4-yloxy)-1'-cyclphenyloxy]-phenyl-
}-2-methoxy-propionic acid (Compound 92);
[0235]
(2S)-(1'S,3'S)-3-{4-[3'-(Biphenyl-4-yloxy)-1'-cyclohexyloxy]-phenyl-
}-2-methoxy-propionic acid (Compound 93);
[0236]
(2S)-3-{4-[3-(4-Benzoyl-phenoxy)-propoxy]-phenyl}-2-methoxy-propion-
ic acid (Compound 94);
[0237]
(2S)-3-(4-{3-[4-(4-Fluoro-benzoyl)-phenoxy]-propoxy}-phenyl)-2-meth-
oxy-propionic acid (Compound 95);
[0238]
(2S)-3-{4-[3-(4-Benzyl-phenoxy)-propoxy]-phenyl}-2-methoxy-propioni-
c acid (Compound 96);
[0239]
(2S)-2-Methoxy-3-{4-[3-(3-phenylamino-phenoxy)-propoxy]-phenyl}-pro-
pionic acid (Compound 97);
[0240]
(2S)-3-{4-[3-Butyl-phenoxy)-propoxy]-phenyl}-2-methoxy-propionic
acid (Compound 98);
[0241]
(2S)-3-(4-{3-[4-(2-Fluoro-benzoyl)-phenoxy]-propoxy}-phenyl)-2-meth-
oxy propionic acid (Compound 99);
[0242]
(2S)-2-Methoxy-3-{4-[3-(9-oxo-9H-fluoren-2-yloxy)-propoxy]-phenyl}--
propionic acid (Compound 100);
[0243]
(2S)-2-Methoxy-3-{4-[3-(2-methyl-benzothiazol-5-yloxy)-propoxy]-phe-
nyl}-propionic acid (Compound 101);
[0244]
(2S)-2-Methoxy-3-{4-[3-(3-morpholinyl-phenoxy)-propoxy]-phenyl}-pro-
pionic acid (Compound 102);
[0245]
(2S)-3-{4-[3-(Biphenyl-2-yloxy)-propoxy]-phenyl}-2-methoxy-propioni-
c acid (Compound 103);
[0246]
(2S)-3-{4-[3-(4-Cylopentyl-phenoxy)-propoxy]-phenyl}-2-methoxy
propionic acid (Compound 104);
[0247]
(2S)-3-{4-[3-(4-Cyano-3-fluoro-phenoxy)-propoxy]-phenyl}-2-methoxy--
propionic acid (Compound 105);
[0248]
(2S)-3-{4-[3-(2,4-Difluoro-phenoxy)-propoxy]-phenyl}-2-methoxy-prop-
ionic acid (Compound 106);
[0249]
(2S)-2-Methoxy-3-{4-[3-(4-trifluoromethyl-phenoxy)-propoxy]-phenyl}-
-propionic acid (Compound 107);
[0250]
(2S)-2-Methoxy-3-{4-[3-(3-trifluoromethyl-phenoxy)-propoxy]-phenyl}-
-propionic acid (Compound 108);
[0251]
(2S)-2-Methoxy-3-{4-[3-(5-oxo-5,6,7,8-tetrahydro-naphthalen-2-yloxy-
)-propoxy]-phenyl}-propionic acid (Compound 109);
[0252]
(2S)-3-{4-[3-(3,5-Difluoro-phenoxy)-propoxy]-phenyl}-2-methoxy-prop-
ionic acid (Compound 110);
[0253]
(2S)-3-{4-[3-(Isoquinolin-5-yloxy)-propoxy]-phenyl}-2-methoxy-propi-
onic acid (Compound 111);
[0254]
(2S)-2-Methoxy-3-{4-[3-(4-trifluoromethoxy-phenoxy)-propoxy]-phenyl-
}-propionic acid (Compound 112);
[0255]
(2S)-3-{4-[3-(4-Fluoro-phenoxy)-propoxy]-phenyl}-2-methoxy-propioni-
c acid (Compound 113);
[0256]
(2S)-2-Methoxy-3-{4-[3-(4-phenylacetyl-phenoxy)-propoxy]-phenyl}-pr-
opionic acid (Compound 114);
[0257]
(2S)-2-Methoxy-3-(4-{3-[4-(1-methyl-1-phenyl-ethyl)-phenoxy]-propox-
y}-phenyl)-propionic acid (Compound 115);
[0258]
(2S)-2-Methoxy-3-{4-[3-(4-oxo-2-phenyl-4H-chromen-7-yloxy)-propoxy]-
-phenyl}-propionic acid (Compound 116);
[0259]
4-{3-[4-(2-Carboxy-2-methoxy-ethyl)-phenoxy]-propoxy}-benzoic acid
benzyl ester (Compound 117);
[0260]
(2S)-2-Methoxy-3-{4-[3-(4-oxo-2-phenyl-chroman-6-yloxy)-propoxy]-ph-
enyl}-propionic acid (Compound 118);
[0261]
(2S)-2-Methoxy-3-{4-[3-(4-oxo-2-phenyl-chroman-6-yloxy)-propoxy]-ph-
enyl}-propionic acid (Compound 119);
[0262]
(2S)-2-Methoxy-3-{4-[3-(4-oxo-2-phenyl-chroman-7-yloxy)-propoxy]-ph-
enyl}-propionic acid (Compound 120);
[0263]
(2S)-2-Methoxy-3-(4-{3-[4-(4-trifluoromethyl-phenoxy)-phenoxy]-prop-
oxy}-phenyl)-propionic acid (Compound 121);
[0264]
(2S)-3-{4-[2-(4-benzoyl-phenoxy)-ethoxy]-phenyl}-2-methoxy-propioni-
c acid (Compound 122);
[0265]
(2S)-3-{4-[2-(Biphenyl-4-yloxy)-ethoxy]-phenyl}-2-methoxy-propionic
acid (Compound 123);
[0266]
(2S)-3-{4-[2-(Biphenyl-4-yloxy)-acetyl]-phenyl}-2-methoxy-propionic
acid (Compound 124);
[0267]
(2S)-2-Methoxy-3-{4-[2-(4-phenoxy-phenoxy)-acetyl]-phenyl}-propioni-
c acid (Compound 125);
[0268]
(2S)-3-{4-[2-(4-Benzoyl-phenoxy)-acetyl]-phenyl}-2-methoxy-propioni-
c acid (Compound 126);
[0269]
(2S)-3-{4-[3-(Biphenyl-4-yloxy)-propyl]-phenyl}-2-methoxy-propionic
acid (Compound 127);
[0270]
(2S)-3-{4-[4-(Biphenyl-4-yloxy)-butyl]-phenyl}-2-methoxy-propionic
acid (Compound 128);
[0271]
(2S)-3-{4-[5-(Biphenyl-4-yloxy)-pentyl]-phenyl}-2-methoxy-propionic
acid (Compound 129);
[0272] 3-{4-[3-(4-Benzoyl-phenoxy)-propoxy]-3-methoxy-propionic
acid (Compound 130);
[0273]
3-(4-{3-[4-(4-Fluoro-benzoyl)-phenoxy]-propoxy}-3-methoxy-phenyl)-2-
-methoxy-propionic acid (Compound 131);
[0274]
3-{4-[3-(Biphenyl-4-yloxy)-propoxy]-3-methoxy-phenyl}-2-methoxy-pro-
pionic acid (Compound 132);
[0275]
2-Methoxy-3-{3-methoxy-4-[3-(4-phenoxy-phenoxy)-propoxy]-phenyl}-pr-
opionic acid (Compound 133);
[0276]
(2S)-3-(4-[3-phenyl-4-yloxy)-propoxy]-3-chloro-phenyl}-2-methoxy-pr-
opionic acid (Compound 134);
[0277]
3-{3-Chloro-4-[3-(4-phenoxy-phenoxy)-propoxy]-phenyl}-2-methoxy-pro-
pionic acid (Compound 135);
[0278]
'3-{4-[3-(4-Benzoyl-phenoxy)-propoxy]-3-chloro-phenyl}-2-methoxy-pr-
opionic acid (Compound 136);
[0279]
3-{4-[3-(Biphenyl-4-yloxy)-propoxy]-3,5-dichloro-6-phenyl}-2-methox-
y-propionic acid (Compound 137);
[0280]
3-{4-[3-(Biphenyl-4-yloxy)-propoxy]-3-fluoro-phenyl}-2-methoxy-prop-
ionic acid (Compound 138);
[0281]
3-{4-[3-(3-(Biphenyl-4-yloxy)-propoxy]-3-trifluoromethyl-phenyl}-2--
methoxy-propionic acid (Compound 139);
[0282]
(2S)-3-{6-[3-(Biphenyl-4-yloxy)-propoxy]-4'-methoxy-biphenyl-3-yl}--
2-methoxy-propionic acid (Compound 140);
[0283]
3-{6-[3-(Biphenyl-4-yloxy)-propoxy]-4'-fluoro-biphenyl-3-yl}-2-meth-
oxy-propionic acid (Compound 141);
[0284]
3-{6-[3-(Biphenyl-4-yloxy)-propoxy]-[1,1';4',1"]terphenyl-3-yl}-2-m-
ethoxy-propionic acid (Compound 142);
[0285]
3-{6-[3-(Biphenyl-4-yloxy)-propoxy]-2'-methoxy-biphenyl-3-yl}-2-met-
hoxy-propionic acid (Compound 143);
[0286]
2-Methoxy-3-{6-[3-(4-phenoxy-phenoxy)-propoxy]-[1,1';4',1"]terpheny-
l-3-yl}-propionic acid (Compound 144);
[0287]
3-{4-[3-(4-Benzoyl-phenoxy)-propoxy]-3-styryl-phenyl}-2-methoxy-pro-
pionic acid (Compound 145);
[0288]
3-(4-{3-[4-(Hydroxy-phenyl-methyl)-phenoxy]-propoxy}-3-phenethyl-ph-
enyl)-2-methoxy-propionic acid (Compound 146);
[0289]
3-{4-[3-(4-Benzyl-phenoxy)-propoxy]-3-phenethyl-phenyl}-2-methoxy-p-
ropionic acid (Compound 147);
[0290]
(2S)-3-{3-Allyl-4-[3-(4-phenoxy-phenoxy)-propoxy]-phenyl}-2-methoxy-
-propionic acid (Compound 148);
[0291]
(2S)-2-Methoxy-3-{4-[3-(4-phenoxy-phenoxy)-propoxy]-3-propyl-phenyl-
}-propionic acid (Compound 149);
[0292]
3-{4-[3-(Biphenyl-4-yloxy)-propoxy]-2-methyl-phenyl}-2-methoxy-acry-
lic acid (Compound 150);
[0293]
3-{4-[3-(Biphenyl-4-yloxy)-propoxy]-2-methyl-phenyl}-2-methoxy-prop-
ionic acid (Compound 151),
[0294]
3-{3-[3-(Biphenyl-4-yloxy)-propoxy]-phenyl}-2-methoxy-propionic
acid (Compound 152);
[0295]
'2-Methoxy-3-{3-[3-(4-phenoxy-phenoxy)-propoxy]-phenyl}-propionic
acid (Compound 153);
[0296]
3-{3-[3-(4-Benzoyl-phenoxy)-propoxy]-phenyl}-2-methoxy-propionic
acid (Compound 154);
[0297]
2-Methoxy-3-{3-[5-(4-phenoxy-phenoxy)-pent-1-ynyl]-phenyl}-propioni-
c acid (Compound 155);
[0298]
2-Methoxy-3-{3-[5-(4-phenoxy-phenoxy)-pentyl]-phenyl}-propionic
acid (Compound 156);
[0299]
2-Methoxy-3-{3-[5-(4-phenoxy-phenoxy)-pentanoyl]-phenyl}-propionic
acid (Compound 157);
[0300]
3-{4-[3-(3-Allyl-biphenyl-4-yloxy)-propoxy]-phenyl}-2-methoxy-propi-
onic acid (Compound 158);
[0301]
(2S)-2-Methoxy-3-{4-[3-(3-propyl-biphenyl-4-yloxy)-propoxy]-phenyl}-
-propionic acid (Compound 159);
[0302]
(2S)-3-{4-[3-(2-Allyl-4-phenoxy-phenoxy)-propoxy]-phenyl}-2-methoxy-
-propionic acid (Compound 160);
[0303]
(2S)-2-Methoxy-3-{4-[3-(4-phenoxy-2-propyl-phenoxy)-propoxy]-phenyl-
}-propionic acid (Compound 161);
[0304]
3-{4-[3-(Biphenyl-4-yloxy)-propoxy]-3-methyl-phenyl}-2-methoxy-prop-
ionic acid (Compound 162);
[0305]
2-Methoxy-3-{3-methyl-4-[3-(4-phenoxy-phenoxy)-propoxy]-phenyl}-pro-
pionic acid (Compound 163);
[0306]
3-{4-[3-(4-Benzoyl-phenoxy)-propoxy]-3-methyl-phenyl]-2-methoxy-pro-
pionic acid (Compound 164);
[0307]
(2S)-3-{4-[3-(Dibenzofuran-2-yloxy)-propoxy]-phenyl}-2-methoxy-prop-
ionic acid (Compound 165);
[0308]
(2S)-3-[4-(3-{4-[(4-Fluoro-phenyl)-hydroxyimino-methyl]-phenoxy}-pr-
opoxy)-phenyl]-2-methoxy-propionic acid (Compound 166);
[0309]
(2S)-3-[4-(3-{4-[(4-Fluoro-phenyl)-hydroxy-methyl]-phenoxy}-propoxy-
)-phenyl]-2-methoxy-propionic acid (Compound 167);
[0310]
(2S)-2-Methoxy-3-(4-{3-[4-(4-piperidin-1-yl-benzoyl)-phenoxy]-propo-
xy}-phenyl)-propionic acid (Compound 168);
[0311]
(2S)-2-Methoxy-3-(4-{3-[4-(4-morpholin-4-yl-benzoyl)-phenoxy]-propo-
xy}-phenyl)-propionic acid (Compound 169);
[0312]
(2S)-3-(4-{3-[4-(4-Hydroxy-benzoyl)-phenoxy]-propoxy}-phenyl)-2-met-
hoxy-propionic acid (Compound 170);
[0313]
(2S)-2-methoxy-3-{4-[3-(4-phenoxy-phenoxy)-propoxy]phenyl}propanoic
acid sodium salt (Compound 171);
[0314]
(2S)-3-[4-(3-{4-[Hydroxyimino-(4-hydroxy-phenyl)-methyl]-phenoxy}-p-
ropoxy)-phenyl]-2-methoxy-propionic acid (Compound 172);
[0315]
(2S)-3-{4-[3-(4-Benzoyl-3-hydroxy-phenoxy)-propoxy]-phenyl}-2-metho-
xy-propionic acid (Compound 173);
[0316]
(2S)-3-(4-{3-[4-(2,4-Dimethoxy-benzoyl)-phenoxy]-propoxy}-phenyl)-2-
-methoxy-propionic acid (Compound 174);
[0317]
3-{4-[3-(4-Benzyl-phenoxy)-propoxy]-3-methoxy-phenyl}-2-methoxy-pro-
pionic acid (Compound 175);
[0318] (S)-3-(4-benzyloxy-phenyl)-2-isopropoxy-propionic acid
(Compound 176);
[0319]
(2S)-2-isopropoxy-3-(4-[3-(4-phenoxy-phenoxy)-propoxy]phenyl}propan-
oic acid sodium salt (Compound 176A);
[0320]
2-Methoxy-3-{3-methoxy-4-[3-phenylacetyl-phenoxy)-propoxy]-phenyl}--
propionic acid (Compound 177);
[0321]
3-{4-[3-(4-Butoxy-phenoxy)-propoxy]-3-methoxy-phenyl}-2-methoxy-pro-
pionic acid (Compound 178);
[0322]
2-Methoxy-3-{3-methoxy-4-[3-(4-oxo-2-phenyl-4H-chromen-6-yloxy)-pro-
poxy]-phenyl}-propionic acid (Compound 179);
[0323]
2-Methoxy-3-(3-methoxy-4-{3-[4-(4-trifluoromethyl-phenoxy)-phenoxy]-
-propoxy}-phenyl)-propionic acid (Compound 180);
[0324]
3-{4-[3-(4-Benzyloxy-phenoxy)-propoxy]-3-methoxy-phenyl}-2-methoxy--
propionic acid (Compound 118);
[0325]
3-{4-[3-(4-Dibenzofuran-3-yl-phenoxy)-propoxy]-3-methoxy-phenyl}-2--
methoxy-propionic acid (Compound 182);
[0326]
(2S)-3-{4-[4-(Biphenyl-4-yloxy)-butoxy]-phenyl}-2-methoxy-propionic
acid (Compound 183);
[0327]
(2S)-3-{4-[4-(4-Benzoyl-phenoxy)-butoxy]-phenyl}-2-methoxy-propioni-
c acid (Compound 184);
[0328]
(2S)-2-Methoxy-3-{4-[4-(4-phenoxy-phenoxy)-butoxy]-phenyl}-propioni-
c acid (Compound 185);
[0329]
(2S)-2-Methoxy-3-{4-[2-(2,3,6-trifluoro-phenoxy)ethoxy]-phenyl}-pro-
pionic acid (Compound 186);
[0330]
(2S)-3-[4-(3-Benzyloxy-benzyloxy)-phenyl]-2-methoxy-propionic acid
(Compound 187);
[0331]
3-{4-[3-(Biphenyl-4-yloxy)-propoxy]-2-methoxy-phenyl}-2-methoxy-pro-
pionic acid (Compound 188);
[0332]
3-{4-[3-(4-Benzoyl-phenoxy)-propoxy]-2-methoxy-phenyl}-2-methoxy-pr-
opionic acid (Compound 189);
[0333]
2-Methoxy-3-{2-methoxy-4-[3-(4-phenoxy-phenoxy)-propoxy]-phenyl}-pr-
opionic acid (Compound 190);
[0334]
3-{4-[3-(Biphenyl-4-yloxy)-propoxy]-2-chloro-phenyl}-2-methoxy-prop-
ionic acid (Compound 191);
[0335]
3-{2-Chloro-4-[3-(4-phenoxy-phenoxy)-propoxy]-phenyl}-2-methoxy-pro-
pionic acid (Compound 192);
[0336]
3-{4-[3-(4-Benzoyl-phenoxy)-propoxy]-2-chloro-phenyl}-2-methoxy-pro-
pionic acid (Compound 193);
[0337]
(2S)-4-{3-[4-(2-Carboxy-2-methoxy-ethyl-phenoxy]-propoxy}-benzoic
acid (Compound 194);
[0338]
(2S)-3-{4-[3-(4-Dibenzothiophen-4-yl-phenoxy)-propoxy]-phenyl}-2-me-
thoxy-propionic acid (Compound 195);
[0339]
(2S)-3-{4-[3-(4'-Hydroxy-biphenyl-4-yloxy)-propoxy]-phenyl}-2-metho-
xy-propionic acid (Compound 196);
[0340]
(2S)-4'-{3-[4-(2-Carboxy-2-methoxy-ethyl)-phenoxy]-propoxy}-bipheny-
l-4-carboxylic acid (Compound 197);
[0341]
(2S)-3-{4-[2-(4-Benzoyl-phenoxy)-cyclohexyloxy]-phenyl}-2-methoxy-p-
ropionic acid (Compound 198);
[0342]
(2S)-3-(4-{2-[4-(4-Fluoro-benzoyl)-phenoxy]-cyclohexyloxy}-phenyl)--
2-methoxy-propionic acid (Compound 199);
[0343]
(2S)-3-(4-{3-[3-(4-Fluoro-phenyl)-benzofuran-6-yloxy]-propoxy}-phen-
yl)-2-methoxy-propionic acid (Compound 200);
[0344]
(2S)-2-Methoxy-3-{4-[3-(5,6,7,8-tetrahydro-naphthalen-2-yloxy)-prop-
oxy]-phenyl}-propionic acid (Compound 201);
[0345]
(2S)-3-{4-[3-(4-Benzyloxy-phenoxy)-propoxy]-phenyl}-2-methoxy-propi-
onic acid (Compound 202);
[0346]
(2S)-3-{4-[3-(4-Benzyloxy-phenoxy)-propoxy]-phenyl}-2-methoxy-propi-
onic acid (Compound 203);
[0347]
(2S)-3-{4-[3-(4-Heptyloxy-phenoxy)-propoxy]-phenyl}-2-methoxy-propi-
onic acid (Compound 204);
[0348] (2S)-3-{4-[3-(6-Benzoyl-naphthalen-2
yloxy)-propoxy]-phenyl}-2-meth- oxy-propionic acid (Compound
205);
[0349]
(2S)-3-{4-[3-(Benzo[1,3]dioxol-5-yloxy)-propoxy]-phenyl}-2-methoxy--
propionic acid (Compound 206);
[0350]
(2S)-3-{4-[3-(9H-Fluoren-2-yloxy)-propoxy]-phenyl}-2-methoxy-propio-
nic acid (Compound 207);
[0351]
(2S)-2-Methoxy-3-{4-[3-(4-octyl-phenoxy)-propoxy]-phenyl}-propionic
acid (Compound 208);
[0352]
(2S)-2-Methoxy-3-{4-[3-(naphthalen-1-yloxy)-propoxy]-phenyl}-propio-
nic acid (Compound 209);
[0353]
(2S)-3-{4-[3-(1H-Indol-7-yloxy)-propoxy]-phenyl}-2-methoxy-propioni-
c acid (Compound 210);
[0354]
(2S)-3-{4-[3-(4'-Fluoro-biphenyl-4-yloxy)-propoxy]-phenyl}-2-methox-
y-propionic acid (Compound 211);
[0355]
(2S)-3-{4-[3-(4'-Chloro-biphenyl-4-yloxy)-propoxy]-phenyl}-2-methox-
y-propionic acid (Compound 212);
[0356]
(2S)-3-{4-[3-(3',5'-Bis-trifluoromethyl-biphenyl-4-yloxy)-propoxy]--
phenyl}-2-methoxy-propionic acid (Compound 213);
[0357]
(2S)-3-{4-[3-(4-Dibenzofuran-4-yl-phenoxy)-propoxy]-phenyl}-2-metho-
xy-propionic acid (Compound 214);
[0358]
(2S)-2-Methoxy-3-{4-[3-(4'-phenoxy-biphenyl-4-yloxy)-propoxy]-pheny-
l}-propionic acid (Compound 215);
[0359]
(2S)-2-Methoxy-3-{4-[3-(4-thiophen-2-yl-phenoxy)-propoxy]-phenyl}-p-
ropionic acid (Compound 216);
[0360]
(2S)-3-{4-[3-(3'-Chloro-biphenyl-4-yloxy)-propoxy]-phenyl}-2-methox-
y-propionic acid (Compound 217);
[0361]
(2S)-3-{4-[3-(2'-Chloro-biphenyl-4-yloxy)-propoxy]-phenyl}-2-methox-
y-propionic acid (Compound 218);
[0362]
(2S)-3-{4-[3-(2'-Fluoro-biphenyl-4-yloxy)-propoxy]-phenyl}-2-methox-
y-propionic acid (Compound 219);
[0363]
(2S)-3-{4-[3-(4-Benzo[1,3]dioxol-5-yl-phenoxy)-propoxy]-phenyl}-2-m-
ethoxy-propionic acid (Compound 220);
[0364]
(2S)-3-{4-[3-(4'-tert-Butyl-biphenyl-4-yloxy)-propoxy]-phenyl}-2-me-
thoxy-propionic acid (Compound 221);
[0365]
(2S)-2-Methoxy-3-{4-[3-(3'-trifluoromethoxy-biphenyl-4-yloxy)-propo-
xy]-phenyl}-propionic acid (Compound 222);
[0366]
(2S)-2-Methoxy-3-{4-[3-(4'-trifluoromethoxy-biphenyl-4-yloxy)-propo-
xy]-phenyl}-propionic acid (Compound 223);
[0367]
(2S)-3-(4-{3-[4-(2-Chloro-benzoylamino)-phenoxy]-propoxy}-phenyl)-2-
-methoxy-propionic acid (Compound 224);
[0368]
(2S)-2-Methoxy-3-(4-{3-[4-(2-methoxy-benzoylamino)-phenoxy]-propoxy-
}-phenyl)-propionic acid (Compound 225);
[0369]
(2S)-3-(4-{3-[4-(2,2-Dimethyl-propionylamino)-phenoxy)-propoxy}-phe-
nyl)-2-methoxy-propionic acid (Compound 226);
[0370]
(2S)-3-(4-{3-[4-(3-Fluoro-benzoylamino)-phenoxy]-propoxy}-phenyl)-2-
-methoxy-propionic acid (Compound 227);
[0371]
(2S)-2-Methoxy-3-(4-{3-[4-(3-methoxy-benzoylamino)-phenoxy]-propoxy-
}-phenyl)-propionic acid (Compound 228);
[0372]
(2S)-2-Methoxy-3-(4-{3-[4-(3-methyl-benzoylamino)-phenoxy]-propoxy}-
-phenyl)-propionic acid (Compound 229);
[0373]
(2S)-3-(4-{3-[4-(4-Fluoro-benzoylamino)-phenoxy]-propoxy}-phenyl)-2-
-methoxy-propionic acid (Compound 230);
[0374]
(2)-3-(4-{3-[4-(4-Chloro-benzoylamino)-phenoxy]-propoxy}-phenyl)-2--
methoxy-propionic acid (Compound 231);
[0375]
(2S)-2-Methoxy-3-(4-{3-[4-(4-methoxy-benzoylamino)-phenoxy]-propoxy-
}-phenyl)-propionic acid (Compound 232);
[0376]
(2S)-2-Methoxy-3-{4-[3-(4-phenylacetylamino-phenoxy)-propoxy]-pheny-
l}-propionic acid (Compound 233);
[0377]
(2S)-3-(4-{3-[4-(2-Chloro-benzoyl)-phenoxy]-propoxy}-phenyl)-2-meth-
oxy-propionic acid (Compound 234);
[0378]
(2S)-2-Methoxy-3-(4-{3-[4-naphthalene-1-carbonyl)-phenoxy]-propoxy}-
-phenyl)-propionic acid (Compound 235);
[0379]
(2S)-3-(4-{3-[4-(3-Fluoro-benzoyl)-phenoxy]-propoxy}-phenyl)-2-meth-
oxy-propionic acid (Compound 236);
[0380]
(2S)-2-Methoxy-3-(4-{3-[4-(3-methoxy-benzoyl)-phenoxy]-propoxy}-phe-
nyl)-propionic acid (Compound 237);
[0381]
(2S)-2-Methoxy-3-(4-{3-[4-(naphthalene-2-carbonyl)-phenoxy]-propoxy-
}-phenyl)-propionic acid (Compound 238);
[0382]
(2S)-2-Methoxy-3-(4-{3-[4-(4-methyl-benzoyl)-phenoxy]-propoxy}-phen-
yl)-propionic acid (Compound 239);
[0383]
(2S)-3-(4-{3-[4-(2,2-Dimethyl-propionyl)-phenoxy]-propoxy}-phenyl)--
2-methoxy-propionic acid (Compound 240);
[0384]
(2S)-3-{4-[3-(4-Isobutyryl-phenoxy)-propoxy]-phenyl}-2-methoxy-prop-
ionic acid (Compound 241);
[0385]
(2S)-2-Methoxy-3-(4-{3-[4-(3-phenyl-propionyl)-phenoxy-]propoxy}-ph-
enyl)-propionic acid (Compound 242);
[0386]
3-{4-[3-(Biphenyl-4-yloxy)-propoxy]-2-fluoro-phenyl}-2-methoxy-prop-
ionic acid (Compound 243);
[0387] 2-phenoxy-3-[4-(4-phenoxy-phenoxy)propoxyphenyl]propanoic
acid (Compound 244);
[0388]
(2S,2'S)-3-(4-{3-[4-(2'-Carboxy-2'-methoxy-ethyl)-phenoxy]-propoxy}-
-phenyl)-2-methoxy-propionic acid (Compound 245);
[0389] .alpha.-Methoxycinnamate Intermediate, ethyl
(2S)-2-methoxy-3-(4-hydroxyphenyl) propanoate (Compound 246);
[0390]
(2S)-2-methoxy-3-{4-[3-(4-phenoxy-phenoxy)-propoxy]phenyl}propanoic
acid (Compound 247);
[0391]
(2S)-(2'RS)-2-Methoxy-{4-[2'-methyl-3-(4-phenoxy-phenoxy)-propoxy]--
phenyl}-propionic acid (Compound 248);
[0392] 2(S)-3-[4-(3-Benzyloxy-propoxy)-phenyl]-2-methoxypropionic
acid (Compound 249);
[0393] (2S)-3-[4-(5-Benzyloxy-pentyloxy)-phenyl]-2-methoxypropionic
acid (Compound 250);
[0394]
(2S)-2-ethoxy-{4-[3-(4-phenoxy-phenoxy)-propoxyl]-phenyl}-propionic
acid (Compound 251);
[0395]
(2S)-2-Benzyloxy-3-{4-[3-(4-phenoxy-phenoxy)-propoxy]-phenyl}-propi-
onic acid (Compound 252);
[0396] (2S)-3-{4-[3-(4-{4-[2-(tert-Butyl
dimethyl-silanyloxy)-ethoxy]-benz-
oyl}-phenoxy)-propoxy]-phenyl}-2-methoxy-propionic acid (Compound
253);
[0397]
(2S)-3-[4-(3-{4-[4-(2-Hydroxy-ethoxy)-benzoyl]-phenoxy}-propoxy)-ph-
enyl]-2-methoxy-propionic acid (Compound 254);
[0398]
(2S)-3-{4-[3-(4-phenoxy-phenoxy)-propoxy]-phenyl}-2-propoxy-propion-
ic acid (Compound 255);
[0399]
(2S)-3-{4-[3-(4-Benzoyl-phenoxy)-propoxy]-phenyl}-2-ethoxy-propioni-
c acid (Compound 256);
[0400]
(2S)-3-{4-[3-(4-Benzyl-phenoxy)-propoxy]-phenyl}-2-ethoxy-propionic
acid (Compound 257);
[0401]
(2S)-3-{4-[3-(4-Benzoyl-phenoxy)-propoxy]-3-chloro-phenyl}-2-methox-
y-propionic acid (Compound 258);
[0402]
(2S)-4'-{3-[4-(2-Carboxy-2-methoxy-ethyl)-2-methoxy-phenoxy]-propox-
y}-biphenyl-4-carboxylic acid (Compound 259);
[0403]
(2S)-3-{4-[3-(4'-tert-Butyl-biphenyl-4-yloxy)-propoxy]-2-methoxy-pr-
opionic acid (Compound 260);
[0404]
(2S)-3-(4-{3-[4-(4-Hydroxy-phenoxy)-phenoxy]-propoxy}-phenyl)-2-met-
hoxy-propionic acid (Compound 261);
[0405]
(2S)-2-Methoxy-3-(4-{3-[4-(2,2,3,3-tetrafluoro-propoxy)-phenoxy]-pr-
opoxy}-phenyl)-propionic acid (Compound 262);
[0406]
(2S)-2-Methoxy-3-(4-{3-[4-(3-methyl-butoxy)-phenoxy]-propoxy}-pheny-
l)-propionic acid (Compound 263);
[0407]
(2S)-3-3-{4-[3-(4-Isobutoxy-phenoxy)-propoxy]-phenyl}-2-methoxy-pro-
pionic acid (Compound 264);
[0408]
(2S)-3-{4-[3-(4-Isopropoxy-phenoxy)-propoxy]-phenyl}-2-methoxy-prop-
ionic acid (Compound 265);
[0409]
(2S)-3-{4-[3-(4-Cyclohexylmethoxy-phenoxy)-propoxy]-phenyl}-2-metho-
xy-propionic acid (Compound 266);
[0410]
(2S)-2-Methoxy-3-{4-[3-(4-phenetyloxy-phenoxy)-propoxy]-phenyl}-pro-
pionic acid (Compound 267);
[0411]
(2S)-3-(4-{3-[4-(3-Dimethylamino-propoxy)-phenoxy]-propoxy}-phenyl)-
-2-methoxy-propionic acid (Compound 268);
[0412]
(2S)-3-{4-[3-(4-Carboxymethoxy-phenoxy)-propoxy]-phenyl}-2-methoxy--
propionic acid (Compound 269);
[0413]
(2S)-3-(4-{3-[4-(1H-Indol-5-yl)-phenoxy]-propoxy}-phenyl)-2-methoxy-
-propionic acid (Compound 270);
[0414]
(2S)-Methoxy-3-{4-[3-(4-pyridin-3-yl-phenoxy)-propoxy]-phenyl}-prop-
ionic acid (Compound 271);
[0415]
(2S)-2-Methoxy-3-{4-[3-(4-pyridin-4-yl-phenoxy)-propoxy]-phenyl}-pr-
opionic acid (Compound 272);
[0416]
(2S)-2-Methoxy-3-{4-[3-(4-quinolin-8-yl-phenoxy)-propoxy]-phenyl}-p-
ropionic acid (Compound 273);
[0417]
(2S)-3-{4-[3-(4'-Cyano-biphenyl-4-yloxy)-propoxy]-phenyl}-2-methoxy-
-propionic acid (Compound 274);
[0418]
(2S)-2-Methoxy-3-(4-{3-[4)-(1H-tetrazol-5-yl)biphenyl-4-yloxy]-prop-
oxy}-phenyl)-propionic acid (Compound 275);
[0419]
(2)-3-{4-[3-(4-Imidazol-1-yl-phenoxy)-propoxy]-phenyl}-2-methoxy-pr-
opionic acid (Compound 276);
[0420]
(2S)-3-(4-{3-[4-(1,3-Dioxo-1,3-dihydro-isoindol-2-yl)-phenoxy]-prop-
oxy}-phenyl)-2-methoxy-propionic acid (Compound 277);
[0421]
(2S)-3-(4-{3-[4-(4-Acetyl-piperazin-1-yl)-phenoxy]-propoxy}-phenyl)-
-2-methoxy-propionic acid (Compound 278);
[0422]
(2S)-2-Methoxy-3-{4-[3-(4-piperazin-1-yl-phenoxy)-propoxy]-phenyl}--
propionic acid (Compound 279);
[0423]
(2S)-2-Methoxy-3-{4-[3-(4-morpholin-4-yl-phenoxy)-propoxy]-phenyl}--
propionic acid (Compound 280);
[0424]
(2S)-3-{4-[3-(Biphenyl-4-yloxy)-propoxy]-2-chloro-phenyl)-2-methoxy-
-propionic acid (Compound 281);
[0425]
3-{4-[3-(4-Benzoyl-phenoxy)-propoxy]-2-chloro-phenyl}-2-methoxy-pro-
pionic acid (Compound 282);
[0426]
(2S)-3-{4-[2-(biphenyl-4-yloxy)-ethoxy]-phenyl}-2-methoxy-propionic
acid (Compound 283);
[0427]
(2S)-2-methoxy-3-{4-[3-(3-trifluoromethyl-phenoxy)-propoxy]-phenyl}-
-propionic acid (Compound 284);
[0428] (2S)-2-methoxy-3-[4-(3-phenoxy-propoxy)-phenyl]-propionic
acid (Compound 285);
[0429]
(2S)-3-{4-[3-(biphenyl-3-yloxy)-propoxy]-phenyl}-2-methoxy-propioni-
c acid (Compound 286);
[0430]
(2S)-2-methoxy-3-{4-[3-(2-methyl-benzothiazol-5-yloxy)-propoxy)-phe-
nyl]-propionic (Compound 287);
[0431]
(2S)-2-methoxy-3-{4-[3-(3-morpholin-4-yl-phenoxy)-propoxy]-phenyl}--
propionic acid (Compound 288);
[0432]
(2S)-2-methoxy-3-{4-[3-(5,6,7,8-tetrahydro-naphthalen-2-yloxy)-prop-
oxy]-phenyl}-propionic acid (Compound 289);
[0433]
2-methoxy-3-{4-[2-(4-phenoxy-phenoxy)-ethoxy-phenyl)-propionic acid
(Compound 290);
[0434]
3-{3-[3-(biphenyl-4-yloxy)-propoxy]-phenyl}-2-methoxy-propionic
acid (isomer 1) (Compound 291);
[0435]
3-{3-[3-(biphenyl-4-yloxy)-propoxy]-phenyl}-2-methoxy-propionic
acid (Isomer 2) (Compound 292);
[0436]
(2S)-3-{4-[3-(2-cyano-phenoxy)-propoxy]-phenyl}-2-methoxy-propionic
acid (Compound 293);
[0437]
(2S)-2-methoxy-3-{4-[3-(2-methoxy-phenoxy)-propoxy]-phenyl}-propion-
ic acid (Compound 294);
[0438]
(2S)-2-{3-[4-(2-carboxy-2-methoxy-ethyl)-phenoxy]-propoxy}-benzoic
acid (Compound 295);
[0439]
(2S)-3-{4-[3-(3-cyano-phenoxy)-propoxy]-phenyl}-2-methoxy-propionic
acid (Compound 296);
[0440]
(2S)-3-{4-[3-(3-dimethylamino-phenoxy)-propoxy]-phenyl}-2-methoxy-p-
ropionic acid (Compound 297);
[0441]
(2S)-3-{3-[4-(2-carboxy-2-methoxy-ethyl)-phenoxy]-propoxy}-benzoic
acid (Compound 298);
[0442]
(2S)-3-{4-[3-(indan-5-yloxy)-propoxy]-phenyl}-2-methoxy-propionic
acid (Compound 299);
[0443]
(2S)-2-methoxy-3-{4-[3-(naphthalen-2-yloxy)-propoxy]-phenyl}-propio-
nic acid (Compound 300);
[0444]
(2S)-3-{4-[3-(1H-indol-5-yloxy)-propoxy]phenyl}-2-methoxy-propionic
acid (Compound 301);
[0445]
(2S)-2-methoxy-3-{4-[3-(quinolin-6-yloxy)-propoxy]-phenyl}-propioni-
c acid (Compound 302);
[0446]
(2S)-2-methoxy-3-{4-[3-(3-methoxy-phenoxy)-propoxy]-phenyl}-propion-
ic acid (Compound 303);
[0447]
(2S)-3-{4-[3-(3-fluoro-phenoxy)-propoxy]-phenyl}-2-methoxy-propioni-
c acid (Compound 304);
[0448]
(2S)-3-{4-[3-(2-isopropyl-phenoxy)-propoxy]-phenyl}-2-methoxy-propi-
onic acid (Compound 305);
[0449] (2S)-2-methoxy-3-[4-(2-phenoxy-ethoxy)-phenyl]-propionic
acid (Compound 306);
[0450]
(2S)-3-{4-[2-(2-cyano-phenoxy)-ethoxy]-phenyl}-2-methoxy-propionic
acid (Compound 307);
[0451]
(2S)-2-methoxy-3-{4-[2-(2-methoxy-phenoxy)-ethoxy]-phenyl}-propioni-
c acid (Compound 308);
[0452]
(2S)-3-{4-[2-(biphenyl-2-yloxy)-ethoxy]-phenyl}-2-methoxy-propionic
acid (Compound 309);
[0453]
(2S)-2-{2-[4-(2-carboxy-2-methoxy-ethyl)-phenoxy]-ethoxy}-benzoic
acid (Compound 310);
[0454]
(2S)-3-{4-[2-(2-isopropyl-phenoxy)-ethoxy]-phenyl}-2-methoxy-propio-
nic acid (Compound 311);
[0455]
(2S)-3-{4-[2-(3-cyano-phenoxy)-ethoxy]-phenyl}-2-methoxy-propionic
acid (Compound 312);
[0456]
(2S)-3-{4-[2-(3-dimethylamino-phenoxy)-ethoxy]-phenyl}-2-methoxy-pr-
opionic (Compound 313);
[0457]
(2S)-3-{4-[2-(biphenyl-3-yloxy)-ethoxy]-phenyl}-2-methoxy-propionic
acid (Compound 314);
[0458]
(2S)-3-{2-[4-(2-carboxy-2-methoxy-ethyl)-phenoxy]-ethoxy}-benzoic
acid (Compound 315);
[0459]
(2S)-3-{4-[2-(indan-5-yloxy)-ethoxy]-phenyl}-2-methoxy-propionic
acid (Compound 316);
[0460]
(2S)-2-methoxy-3-{4-[2-(naphthalen-2-yloxy)-ethoxy]-phenyl}-propion-
ic acid (Compound 317);
[0461]
(2S)-2-Methoxy-3-{4-[2-(quinolin-6-yloxy)-ethoxy]-phenyl}-propionic
acid (Compound 318);
[0462]
(2S)-2-Methoxy-3-{4-[2-(3-morpholin-4-yl-phenoxy)-ethoxy]-phenyl}-p-
ropionic acid (Compound 319);
[0463]
(2S)-2-methoxy-3-{4-[2-(2-methyl-benzothiazol-5-yloxy)-ethoxy]-phen-
yl}-propionic (Compound 320);
[0464]
(2S)-2-methoxy-3-{4-[2-(3-methoxy-phenoxy)-ethoxy]-phenyl}-propioni-
c acid (Compound 321);
[0465]
(2S)-3-{4-[2-(3-fluoro-phenoxy)-ethoxy]-phenyl}-2-methoxy-propionic
acid (Compound 322);
[0466] 2-methoxy-3-[3-(3-phenoxy-propoxy)-phenyl]-propionic acid
(isomer 1) (Compound 323);
[0467]
3-{3-[3-(2-cyano-phenoxy)-propoxy]-phenyl}-2-methoxy-propionic acid
(isomer 1) (Compound 324);
[0468]
3-{3-[3-(3-cyano-phenoxy)-propoxy]-phenyl}-2-methoxy-propionic acid
(isomer 1) (Compound 325);
[0469] 2-methoxy-3-[3-(3-phenoxy-propoxy)-phenyl]-propionic acid
(isomer 2) (Compound 326);
[0470]
3-{3-[3-(2-cyano-phenoxy)-propoxy]-phenyl}-2-methoxy-propionic acid
(isomer 2) (Compound 327);
[0471]
3-{3-[3-(3-cyano-phenoxy)-propoxy]-phenyl}-2-methoxy-propionic acid
(isomer 2) (Compound 328);
[0472]
2-methoxy-3-{3-[3-(2-methoxy-phenoxy)-propoxy]-phenyl}-propionic
acid (isomer 1) (Compound 329);
[0473]
2-methoxy-3-{3-[3-(2-methoxy-phenoxy)-propoxy]-phenyl}-propionic
acid (isomer 2) (Compound 330);
[0474]
3-{3-[3-(2-isopropyl-phenoxy)-propoxy]-phenyl}-2-methoxypropionic
acid (isomer 1) (Compound 331);
[0475]
3-{3-[3-(2-isopropyl-phenoxy)-propoxy]-phenyl}-2-methoxy-propionic
acid (isomer 2) (Compound 332);
[0476] 3-{3-[3-(2-carboxy-2-methoxy-etyl)-phenoxy]-propoxy}-benzoic
acid (isomer 1) (Compound 333);
[0477]
3-{3-[3-(2-carboxy-2-methoxy-ethyl)-phenoxy]-propoxy}-benzoic acid
(isomer 2) (Compound 334);
[0478]
2-methoxy-3-{3-[3-(3-methoxy-phenoxy)-propoxy]-phenyl}-propionic
acid (isomer 1) (Compound 335);
[0479]
2-methoxy-3-{3-[3-(3-methoxy-phenoxy)-propoxy]-phenyl}-propionic
acid (isomer 2) (Compound 336);
[0480]
2-methoxy-3-{3-[3-(naphthalen-2-yloxy)-propoxy]-phenyl}-propionic
acid (isomer 1) (Compound 337);
[0481]
2-methoxy-3-{3-[3-(naphthalen-2-yloxy)-propoxy]-phenyl}-propionic
acid (isomer 2) (Compound 338);
[0482]
2-methoxy-3-{3-[3-(2-methyl-benzothiazol-5-yloxy)-propoxy]-phenyl}--
propionic acid (isomer 1) (Compound 339);
[0483]
2-methoxy-3-{3-[3-(2-methyl-benzothiazol-5-yloxy)-propoxy]-phenyl}--
propionic acid (isomer 2) (Compound 340);
[0484]
3-{3-{3-(2-chloro-phenoxy)-propoxy]-phenyl}-2-methoxy-propionic
acid (isomer 1) (Compound 341);
[0485]
3-{3-[3-(2-chloro-phenoxy)-propoxy]-phenyl}-2-methoxy-propionic
acid (isomer 2) (Compound 342);
[0486]
3-{3-[3-(3,4-dimethyl-phenoxy)-propoxy]-phenyl}-2-methoxy-propionic
acid (isomer 1) (Compound 343);
[0487]
3-{3-[3-(3,4-dimethyl-phenoxy)-propoxy]-phenyl}-2-methoxy-propionic
acid (isomer 2) (Compound 344);
[0488]
2-{3-[3-(2-carboxy-2-methoxy-ethyl)-phenoxy]-propoxy}-benzoic acid
(isomer 1) (Compound 345);
[0489]
3-{3-[3-(2-carboxy-2-methoxy-ethyl)-phenoxy]-propoxy}-benzoic acid
(isomer 2) (Compound 346);
[0490]
3-{3-[3-(biphenyl-3-yloxy)-propoxy]-phenyl}-2-methoxy-propionic
acid isomer 1) (Compound 347);
[0491]
3-{3-[3-(biphenyl-3-yloxy)-propoxy]-phenyl}-2-methoxy-propionic
acid (isomer 2) (Compound 348);
[0492]
2-methoxy-3-{3-[3-(quinolin-6-yloxy)-propoxy]-phenyl}-propionic
acid (isomer 1) (Compound 349);
[0493]
2-methoxy-3-{3-[3-(quinolin-6-yloxy)-propoxy]-phenyl}-propionic
acid (isomer 2) (Compound 350);
[0494]
3-{3-[2-(2-isopropyl-phenoxy)-ethoxy]-phenyl}-2-methoxy-propionic
acid (isomer 2) (Compound 351);
[0495]
2-methoxy-3-{3-[2-(3-methoxy-phenoxy)-ethoxy]-phenyl}-propionic
acid (isomer 1) (Compound 352);
[0496]
3-{3-[2-(3-fluoro-phenoxy)-ethoxy]-phenyl}-2-methoxy-propionic acid
(isomer 1) (Compound 353);
[0497]
2-methoxy-3-{3-[2-(5,6,7,8-tetrahydro-naphthalen-2-yloxy)-ethoxy]-p-
henyl}-propionic acid (isomer 1) (Compound 354);
[0498]
2-methoxy-3-{3-[2-(3-methoxy-phenoxy)-ethoxy]-phenyl}-propionic
acid (isomer 2) (Compound 355);
[0499]
3-{3-[2-(3-fluoro-phenoxy)-ethoxy]-phenyl}-2-methoxy-propionic acid
(isomer 2) (Compound 356);
[0500]
2-methoxy-3-{3-[2-(5,6,7,8-tetrahydro-naphthalen-2-yloxy)-ethoxy]-p-
henyl}-propionic acid (isomer 2) (Compound 357);
[0501]
(2S)-2-methoxy-3-{4-[2-(4-trifluoromethyl-phenoxy)-ethoxy]-phenyl}--
propionic acid (Compound 358);
[0502]
(2S)-2-methoxy-3-(4-{2-[4-(1-methyl-1-phenyl-ethyl)-phenoxy]-ethoxy-
}-phenyl)-propionic acid (Compound 359);
[0503]
(2S)-3-{4-[2-(4-benzyl-phenoxy)-ethoxy]-phenyl}-2-methoxy-propionic
acid (Compound 360);
[0504]
(2S)-2-methoxy-3-{4-[2-(4-oxo-2-phenyl-4H-chromen-7-yloxy)-ethoxy]--
phenyl}-propionic acid (Compound 361);
[0505]
(2S)-3-{4-[2-(4-cyclopentyl-phenoxy)-ethoxy]-phenyl}-2-methoxy-prop-
ionic acid (Compound 362);
[0506]
(2S)-3-{4-[2-(9H-fluoren-2-yloxy)-ethoxy]-phenyl}-2-methoxy-propion-
ic acid (Compound 363);
[0507]
(2S)-3-{4-[2-(4-butyl-phenoxy)-ethoxy]-phenyl}-2-methoxy-propionic
acid (Compound 364);
[0508]
(2S)-3-{4-[2-(2'-fluoro-biphenyl-4-yloxy)ethoxy]-phenyl}-2-methoxy--
propionic acid (Compound 365);
[0509]
(2S)-3-(4-{2-[4-(2,2-dimethyl-propionyl)-phenoxy]-ethoxy}-phenyl)-2-
-methoxy-propionic acid (Compound 366);
[0510]
3-(4-{2-[4-(2,2-dimethyl-propionylamino)-phenoxy]-ethoxy}-phenyl)-2-
-methoxy-propionic acid (Compound 367);
[0511]
(2S)-3-(4-{2-[4-(cyclopentanecarbonyl-amino)-phenoxy]-ethoxy}-pheny-
l)-2-methoxy-propionic acid (Compound 368);
[0512]
(2S)-3-[4-(2-{4-[(furan-2-carbonyl)-amino]-phenoxy}-ethoxy)-phenyl]-
-2-methoxy-propionic acid (Compound 369);
[0513]
(2S)-2-methoxy-3-{4-(2-{4-[(pyridine-3-carbonyl)-amino]-phenoxy}-et-
hoxy)-phenyl]-propionic acid (Compound 370);
[0514]
(2S)-2-methoxy-3-{4-[2-(2-pyrrolidin-1-yl-phenoxy)-ethoxy]-phenyl}--
propionic acid (Compound 371);
[0515]
(2S)-2-methoxy-3-{4-[2-(pyridin-2-yloxy)-ethoxy]-phenyl}-propionic
acid (Compound 372);
[0516]
(2S)-2-methoxy-3-{4-[2-(2-morpholin-4-yl-phenoxy)-ethoxy]-phenyl}-p-
ropionic acid (Compound 373);
[0517]
(2S)-3-{4-[2-(4'-tert-butyl-biphenyl-4-yloxy)-ethoxy]-phenyl}-2-met-
hoxy-propionic acid (Compound 374);
[0518]
(2S)-2-ethoxy-3-{4-[2-(4-phenoxy-phenoxy)-ethoxy]-phenyl}-propionic
acid (Compound 375);
[0519]
(2R)-2-ethoxy-3-{4-[2-(4-phenoxy-phenoxy)-ethoxy]-phenyl}-propionic
acid (Compound 376);
[0520]
(2S)-3-{4-[2-(biphenyl-4-yloxy)-ethoxy]-phenyl}-2-propoxy-propionic
acid (Compound 377);
[0521]
3-{3-[3-(biphenyl-4-yloxy)-propoxy]-phenyl}-2-ethoxy-propionic acid
(isomer 1) (Compound 378);
[0522]
3-{3-[3-(biphenyl-4-yloxy)-propoxy]-phenyl}-2-ethoxy-propionic acid
(isomer 2) (Compound 379).
[0523] The present invention also includes compounds represented by
Structural Formula (I), wherein Ar is the corresponding aromatic
group from any one of Compounds 1-379. Preferably, R.sub.1 is para
to the carbon atom bonded to W, W.sub.1 or W.sub.2 and is
represented by Structural Formula (II), more preferably Structural
Formula (III) or (V) and even more preferably Structural Formula
(V).
[0524] Also included are compounds represented by Structural
Formulas (I) or (VI), wherein Phenyl Ring A is the corresponding
phenyl or substituted phenyl group from any one of Compounds 1-379
or from one of the compounds disclosed in Examples 1-379.
Preferably, R.sub.1 is para to the carbon atom bonded to W, W.sub.1
or W.sub.2 and is represented by Structural Formula (II), more
preferably Structural Formula (III) or (IV) and even more
preferably Structural Formula (V).
[0525] Also included are compounds represented by Structural
Formula (I), wherein W is --(CH.sub.2).sub.3--O-- and Ar is the
corresponding aromatic group from any one of Compounds 1-379 or
from one of the compounds disclosed in Examples 1-379. Preferably,
R.sub.1 is para to the carbon atom bonded to W, W.sub.1 or W.sub.2
and is represented by Structural Formula (II), more preferably
Structural Formula (III) or (IV) and even more preferably
Structural Formula (V).
[0526] Also included are compounds represented by Structural
Formula (I), wherein W is --(CH.sub.2).sub.4--O-- and Ar is the
corresponding aromatic group from any one of Compounds 1-379 or
from one of the compounds disclosed in Examples 1-379. Preferably,
R.sub.1 is para to the carbon atom bonded to W, W.sub.1 or W.sub.2
and is represented by Structural Formula (II), more preferably
Structural Formula (III) or (IV) and even more preferably
Structural Formula (V).
[0527] Also included are compounds represented by Structural
Formula (I), wherein W is --(CH.sub.2).sub.5--O-- and Ar is the
corresponding aromatic group from any one of Compounds 1-379 or
from one of the compounds disclosed in Examples 1-379. Preferably,
R.sub.1 is para to the carbon atom bonded to W, W.sub.1 or W.sub.2
and is represented by Structural Formula (II), more preferably
Structural Formula (III) or (IV) and even more preferably
Structural Formula (V).
[0528] Also included are compounds represented by Structural
Formula (I), wherein W is --CH.sub.2--C.ident.CH-- and Ar is the
corresponding aromatic group from any one of Compounds 1-379 or
from one of the compounds disclosed in Examples 1-379. Preferably,
R.sub.1 is para to the carbon atom bonded to W, W.sub.1 or W.sub.2
and is represented by Structural Formula (II), more preferably
Structural Formula (III) or (IV) and even more preferably
Structural Formula (V).
[0529] Also included are compounds represented by Structural
Formula (I), wherein W is {CH.sub.2).sub.2C.ident.CH-- and Ar is
the corresponding aromatic group from any one of Compounds 1-379 or
from one of the compounds disclosed in Examples 1-379. Preferably,
R.sub.1 is para to the carbon atom bonded to W, W.sub.1 or W.sub.2
and is represented by Structural Formula (II), more preferably
Structural Formula (III) or (IV) and even more preferably
Structural Formula (V).
[0530] Also included are compounds represented by Structural
Formula (I), wherein W is --(CH.sub.2).sub.3C.ident.CH-- and Ar is
the corresponding aromatic group from any one of Compounds 1-379 or
from one of the compounds disclosed in Examples 1-379. Preferably,
R.sub.1 is para to the carbon atom bonded to W, W.sub.1 or W.sub.2
and is represented by Structural Formula (II), more preferably
Structural Formula (III) or (IV) and even more preferably
Structural Formula (V).
[0531] Also included are compounds represented by Structural
Formula (I), wherein W is --(CH.sub.2).sub.4--C.ident.CH-- and Ar
is the corresponding aromatic group from any one of Compounds 1-379
or from one of the compounds disclosed in Examples 1-379.
Preferably, R.sub.1 is para to the carbon atom bonded to W, W.sub.1
or W.sub.2 and is represented by Structural Formula (II), more
preferably Structural Formula (III) or (IV) and even more
preferably Structural Formula (V).
[0532] Also included are compounds represented by Structural
Formula (I), wherein W is --(CH.sub.2).sub.5C.ident.CH-- and Ar is
the corresponding aromatic group from any one of Compounds 1-379 or
from one of the compounds disclosed in Examples 1-379. Preferably,
R.sub.1 is para to the carbon atom bonded to W, W.sub.1 or W.sub.2
and is represented by Structural Formula (II), more preferably
Structural Formula (III) or (IV) and even more preferably
Structural Formula (V).
[0533] Also included are compounds represented by Structural
Formula (I), wherein W is --CH.sub.2CO-- and Ar is the
corresponding aromatic group from any one of Compounds 1-379 or
from one of the compounds disclosed in Examples 1-379. Preferably,
R.sub.1 is para to the carbon atom bonded to W, W.sub.1 or W.sub.2
and is represented by Structural Formula (II), more preferably
Structural Formula (III) or (IV) and even more preferably
Structural Formula (V).
[0534] Also included are compounds represented by Structural
Formula (I), wherein W is --(CH.sub.2).sub.2CO-- and Ar is the
corresponding aromatic group from any one of Compounds 1-379 or
from one of the compounds disclosed in Examples 1-379. Preferably,
R.sub.1 is para to the carbon atom bonded to W, W.sub.1 or W.sub.2
and is represented by Structural Formula (II), more preferably
Structural Formula (III) or (IV) and even more preferably
Structural Formula (V).
[0535] Also included are compounds represented by Structural
Formula (I), wherein W is --(CH.sub.2).sub.3CO-- and Ar is the
corresponding aromatic group from any one of Compounds 1-379 or
from one of the compounds disclosed in Examples 1-379. Preferably,
R.sub.1 is para to the carbon atom bonded to W, W.sub.1 or W.sub.2
and is represented by Structural Formula (II), more preferably
Structural Formula (III) or (IV) and even more preferably
Structural Formula (V).
[0536] Also included are compounds represented by Structural
Formula (I), wherein W is represented by the following structural
formula: 19
[0537] and Ar is the corresponding aromatic group from any one of
Compounds 1-379 or from one of the compounds disclosed in Examples
1-379. Preferably, R.sub.1 is para to the carbon atom bonded to W,
W.sub.1 or W.sub.2 and is represented by Structural Formula (II),
more preferably Structural Formula (III) or (IV) and even more
preferably Structural Formula (V).
[0538] Also included are compounds represented by Structural
Formula (I), wherein W is represented by the following structural
formula: 20
[0539] and Ar is the corresponding aromatic group from any one of
Compounds 1-379 or from one of the compounds disclosed in Examples
1-379. Preferably, R.sub.1 is para to the carbon atom bonded to W,
W.sub.1 or W.sub.2 and is represented by Structural Formula (II),
more preferably Structural Formula (III) or (IV) and even more
preferably Structural Formula (V).
[0540] Also included are compounds represented by Structural
Formula (I), wherein Ar--O--W-- is the corresponding group from any
one of Compounds 1-379 or from one of the compounds disclosed in
Examples 1-379. Preferably, R.sub.1 is para to the carbon atom
bonded to W and is represented by Structural Formula (II), more
preferably Structural Formula (III) or (IV) and even more
preferably Structural Formula (V).
[0541] Also included are compounds represented by Structural
Formula (I), wherein Ar is the corresponding aromatic group from
any one of Compounds 1-379 or from one of the compounds disclosed
in Examples 1-379, W is --CH(CH.sub.3)W.sub.3CH(CH.sub.3)O-- and
W.sub.3 is a covalent bond, methylene or ethylene. Preferably,
R.sub.1 is para to the carbon atom bonded to W and is represented
by Structural Formula (II), more preferably Structural Formula
(III) or (IV) and even more preferably Structural Formula (V).
[0542] Also included are compounds represented by Structural
Formula (I), wherein Ar is the corresponding aromatic group from
any one of Compounds 1-379 or from one of the compounds disclosed
in Examples 1-379, W is --W.sub.4C(.dbd.O)W.sub.5O-- or
--W.sub.4C(.dbd.CH.sub.2)W.sub.5O-- and W.sub.4 and W.sub.5 are
independently methylene or ethylene. Preferably, R.sub.1 is para to
the carbon atom bonded to W and is represented by Structural
Formula (II), more preferably Structural Formula (III) or (IV) and
even more preferably Structural Formula (V).
[0543] Prodrugs are compounds of the present invention, which have
chemically or metabolically cleavable groups and become by
solvolysis or under physiological conditions the compounds of the
invention that are pharmaceutically active in vivo. Prodrugs
include acid derivatives well known to practitioners of the art,
such as, for example, esters prepared by reaction of the parent
acidic compound with a suitable alcohol, or amides prepared by
reaction of the parent acid compound with a suitable amine. Simple
aliphatic or aromatic esters derived from acidic groups pendent on
the compounds of this invention are preferred prodrugs. In some
cases it is desirable to prepare double ester type prodrugs such as
(acycloxy)alkyl esters or ((alkoxycarbonyl)oxy)alkyl esters.
Particularly preferred esters as prodrugs are methyl, ethyl,
propyl, isopropyl, n-butyl, isobutyl, tert-butyl, morpholinoethyl,
and N,N-diethylglycolamido.
[0544] Methyl ester prodrugs may be prepared by reaction of the
acid form of a compound of the present invention in a medium such
as methanol with an acid or base esterification catalyst (e.g.,
NaOH, H.sub.2SO.sub.4). Ethyl ester prodrugs are prepared in
similar fashion using ethanol in place of methanol.
[0545] Morpholinylethyl ester prodrugs may be prepared by reaction
of the sodium salt of a compound of the present invention (in a
medium such as dimethylformamide) with 4-(2-chloroethyl)morpholine
hydrochloride (available from Aldrich Chemical Co., Milwaukee, Wis.
USA, Item No. C4,220-3).
[0546] The term "pharmaceutically acceptable" means that the
carrier, diluent, excipients and salt must be compatible with the
other ingredients of the formulation, and not deleterious to the
recipient thereof. Pharmaceutical formulations of the present
invention are prepared by procedures known in the art using
well-known and readily available ingredients.
[0547] Also included in the present invention are pharmaceutically
acceptable salts, hydrates, stereoisomers and solvates of the
compounds of the present invention and mixtures of such compounds,
salts, hydrates, stereoisomers and/or solvates.
[0548] By virtue of its acidic moiety, certain compounds of the
present invention form salts with pharmaceutically acceptable
bases. Such a pharmaceutically acceptable salt may be made with a
base which affords a pharmaceutically acceptable cation, which
includes alkali metal salts (especially sodium and potassium),
alkaline earth metal salts (especially calcium and magnesium),
aluminum salts and ammonium salts, as well as salts made from
physiologically acceptable organic bases such as trimethylamine,
triethylamine, morpholine, pyridine, piperidine, picoline,
dicyclohexylamine, N,N'-dibenzylethylenediamine,
2-hydroxyethylamine, bis-(2-hydroxyethyl)amine,
tri-(2-hydroxyethyl)amine- , procaine, dibenzylpiperidine,
N-benzyl-.beta.-phenethylamine, dehydroabietylamine,
N,N'-bisdehydroabietylamine, glucamine, N-methylglucamine,
collidine, quinine, quinoline, and basic amino acid such as lysine
and arginine. These salts may be prepared by methods known to those
skilled in the art.
[0549] Compounds of the present invention that are substituted with
a basic group, may exist as salts with pharmaceutically acceptable
acids. The present invention includes such salts. Examples of such
salts include hydrochlorides, hydrobromides, sulfates,
methanesulfonates, nitrates, maleates, acetates, citrates,
fumarates, tartrates [e.g. (+)-tartrates, (-)-tartrates or mixtures
thereof including racemic mixtures, succinates, benzoates and salts
with amino acids such as glutamic acid.
[0550] Certain compounds of the present invention may contain one
or more chiral centers, and exist in different optically active
forms. When compounds of the present invention contain one chiral
center, the compounds exist in two enantiomeric forms and the
present invention includes both enatiomers and mixtures of
enantiomers, such as racemic mixtures. The enantiomers may be
resolved by methods known to those skilled in the art, for example
by formation of diastereoisomeric salts which may be separated, for
example, by crystallization; formation of diastereoisomeric
derivatives or complexes which may be separated, for example, by
crystallization, gas-liquid or liquid chromatography, selective
reaction of one enantiomer with an enantiomer-specific reagent, for
example enzymatic esterification; or gas-liquid or liquid
chromatography in a chiral environment, for example on a chiral
support for example silica with a bound chiral ligand or in the
presence of a chiral solvent. It will be appreciated that where the
desired enantiomer is converted into another chemical entity by one
of the separation procedures described above, a further step is
required to liberate the desired enantiomeric form. Alternatively,
specific enantiomers may be synthesized by asymmetric synthesis
using optically active reagents, substrates, catalysts or solvents,
or by converting one enantiomer into the other by asymmetric
transformation.
[0551] When a compound of the present invention has one or more
chiral substituent it may exist in diastereoisomeric forms. The
diastereoisomeric pairs may be separated by methods known to those
skilled in the ark for example chromatography or crystallization
and the individual enantiomers within each pair may be separated as
described above. The present invention includes each
diastereoisomer of such compounds and mixtures thereof.
[0552] Certain compounds of the present invention may exist in
zwitterionic form and the present invention includes each
zwitterionic form and mixtures thereof.
[0553] Certain compounds of the present invention and their salts
may exist in more than one crystal form. Polymorphs of compounds of
the present invention form part of this invention and may be
prepared by crystallization of a given compound under different
conditions. For example, using different solvents or different
solvent mixtures for recrystallization; crystallization at
different temperatures; various modes of cooling, ranging from very
fast to very slow cooling during crystallization. Polymorphs may
also be obtained by heating or melting a compound of the present
invention followed by gradual or fast cooling. The presence of
polymorphs may be determined by solid probe nmr spectroscopy, ir
spectroscopy, differential scanning calorimetry, powder X-ray
diffraction or such other techniques.
[0554] A "subject" is a mammal, preferably a human, but can also be
an animal in need of veterinary treatment, e.g., companion animals
(e.g., dogs, cats, and the like), farm animals (e.g., cows, sheep,
pigs, horses, and the like) and laboratory animals (e.g., rats,
mice, guinea pigs, and the like).
[0555] "Treatment" or "treating", as it is used herein, refers to
both therapeutic treatment and prophylactic treatment. "Therapeutic
treatment" refers to preventing the further progression or
ameliorate the symptoms associated with a disease or condition.
"Prophylactic treatment" refers to inhibiting, preventing or
delaying the onset of the symptoms of a disease or condition in a
subject who is at risk for the disease or condition. "Prophylactic
treatment" also includes reducing the severity of the symptoms of a
disease or condition by treating a subject at rsik for developing
the disease or condition before symptoms appear.
[0556] The language an "effective amount" or "pharmaceutically
effective amount" is intended to include an amount that is
sufficient to mediate a disease or condition and prevent its
further progression or ameliorate the symptoms associated with the
disease or condition. An "effective amount" or "pharmaceutically
effective amount" can also include an amount sufficient to prevent
or delay the onset of a disease or condition in a patient at risk
for developing the disease or condition, i.e., prophylactic
treatment. Such amount when administered prophylactically to a
patient can also be effective to lessen the severity of the
mediated condition. Such an amount is intended to include an amount
that is sufficient to modulate a PPAR receptor, such as a
PPAR.gamma. or PPAR.alpha. receptor, which mediate a disease or
condition. Conditions mediated by PPAR.alpha. or PPAR.gamma.
receptors include diabetes mellitus, cardiovascular disease,
Syndrome X, obesity and gastrointestinal disease. Other such
diseases are described below.
[0557] The compounds of the present invention and the
pharmaceutically acceptable salts, solvates, stereoisomers and
hydrates thereof have valuable pharmacological properties and can
be used in pharmaceutical preparations containing the compound or
pharmaceutically acceptable salts, esters or prodrugs thereof, in
combination with a pharmaceutically acceptable carrier or diluent.
They are useful as therapeutic substances in r treating
(therapeutically or prophylactically) hyperglycemia, dyslipidemia,
Type II diabetes, Type I diabetes, hypertriglyceridemia, syndrome
X, insulin resistance, heart failure, diabetic dyslipidemia,
hyperlipidemia, hypercholesteremia, hypertension, obesity, anorexia
bulimia, polycystic ovarian syndrome, anorexia nervosa
cardiovascular disease (especially atherosclerosis) or other
diseases where insulin resistance is a component or other
diosorders mediated by a PPAR receptor. Suitable pharmaceutically
acceptable carriers include inert solid fillers or diluents and
sterile aqueous or organic solutions. The active compound will be
present in such pharmaceutical compositions in amounts sufficient
to provide the desired dosage amount in the range described herein.
Techniques for formulation and administration of the compounds of
the instant invention can be found in Remington: the Science and
Practice of Pharmacy, 19.sup.th edition, Mack Publishing Co.,
Easton, Pa. (1995).
[0558] For oral administration, the compound or salts thereof can
be combined with a suitable solid or liquid carrier or diluent to
form capsules, tablets, pills, powders, syrups, solutions,
suspensions and the like.
[0559] The tablets, pins, capsules, and the like may also contain a
binder such as gum tragacanth, acacias, corn starch or gelatin;
excipients such as dicalcium phosphate; a disintegrating agent such
as corn starch, potato starch, alginic acid, a lubricant such as
magnesium stearate; and a sweetening agent such as sucrose lactose
or saccharin. When a dosage unit form is a capsule, it may contain,
in addition to materials of the above type, a liquid carrier such
as a fatty oil.
[0560] Various other materials may be present as coatings or to
modify the physical form of the dosage unit. For instance, tablets
may be coated with shellac, sugar or both. A syrup or elixir may
contain, in addition to the active ingredient, sucrose as a
sweetening agent, methyl and propylparabens as preservatives, a dye
and a flavoring such as cherry or orange flavor. Such compositions
and preparations should contain at least 0.1 percent of active
compound. The percentage of active compound in these compositions
may, of course, be varied and may conveniently be between about 2
percent to about 60 percent of the weight of the unit. The amount
of active compound in such therapeutically useful compositions is
such that an effective dosage will be obtained.
[0561] The active compounds can also be administered intranasally
as, for example, liquid drops or spray. For oral or nasal
inhalation, the compounds for use according to the present
invention are conveniently delivered in the form of a dry powder
inhaler; or aerosol spray presentation from pressurized packs or a
nebuliser, with the use of a suitable propellant, e.g.,
dichlorodifluoromethane, trichlorofluoromethane,
dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In
the case of pressurized aerosol the dosage unit may be determined
by providing a valve to deliver a metered amount. Capsules and
cartridges of gelatin for use in an inhaler or insufflator may be
formulated containing a powder mix of the compound and a suitable
powder base such as lactose or starch.
[0562] For parental administration the compounds of the present
invention, or salts thereof can be combined with sterile aqueous or
organic media to form injectable solutions or suspensions. For
example, solutions in sesame or peanut oil aqueous propylene glycol
and the like can be used, as well as aqueous solutions of
water-soluble pharmaceutically acceptable salts of the compounds.
Dispersions can also be prepared in glycerol, liquid polyethylene
glycols and mixtures thereof in oils. Under ordinary conditions of
storage and use, these preparations contain a preservative to
prevent the growth of microorganisms.
[0563] The pharmaceutical forms suitable for injectable use include
sterile aqueous solutions or dispersions and sterile powders for
the extemporaneous preparation of sterile injectable solutions or
dispersions. In all cases, the form must be sterile and must be
fluid to the extent that each syringability exists. It must be
stable under the conditions of manufacture and storage and must be
preserved against any contamination. The carrier can be solvent or
dispersion medium containing, for example, water, ethanol, polyol
(e.g. glycerol, propylene glycol and liquid polyethylene glycol),
propylene glycol and liquid polyethylene glycol), suitable mixtures
thereof, and vegetable oils. The injectable solutions prepared in
this manner can then be administered intravenously,
intraperitoneally, subcutaneously, or intramuscularly, with
intramuscular administration being preferred in humans.
[0564] The compounds may also be formulated in rectal compositions
such as suppositories or retention enemas, e.g., containing
conventional suppository bases such as cocoa butter or other
glycerides.
[0565] In addition, to the formulations described previously, the
compounds may also be formulated as a depot preparation. Such long
acting formulations may be administered by implantation, for
example, subcutaneously or intramuscularly or by intramuscular
injection. Thus, for example, as an emulsion in an acceptable oil,
or ion exchange resins, or as sparingly soluble derivatives, for
example, as sparingly soluble salts.
[0566] The effective dosage of active ingredient employed may vary
depending on the particular compound employed, the mode of
administration, the condition being treated and the severity of the
condition being treated.
[0567] When used herein Syndrome X includes pre-diabetic insulin
resistance syndrome and the resulting complications thereof,
insulin resistance, non-insulin dependent diabetes, dyslipidemia,
hyperglycemia obesity, coagulopathy, hypertension and other
complications associated with diabetes. The methods and treatments
mentioned herein include the above and encompass the therapeutic
treatment and/or prophylaxis of any one of or any combination of
the following: hyperglycemia, dyslipidemia, Type II diabetes, Type
I diabetes, hypertriglyceridemia, syndrome X, insulin resistance,
heart failure, diabetic dyslipidemia, hyperlipidemia,
hypercholesteremia, hypertension, obesity, anorexia bulimia,
polycystic ovarian syndrome, anorexia nervosa, cardiovascular
disease (especially atherosclerosis) or other diseases where
insulin resistance is a component or other diosorders mediated by a
PPAR receptor.
[0568] The compositions are formulated and administered in the same
general manner as detailed herein. The compounds of the instant
invention may be used effectively alone or in combination with one
or more additional active agents depending on the desired target
therapy, Combination therapy includes administration of a single
pharmaceutical dosage formulation which contains a compound of the
present invention and one or more additional active agents, as well
as administration of a compound of the present invention and each
active agent in its own separate pharmaceutical dosage formulation.
For example, a compound of an insulin secretogogue such as
biguanides, thiazolidinediones, sulfonylureas, insulin, or
.alpha.-glucosidose inhibitors can be administered to the patient
together in a single oral dosage composition such as a tablet or
capsule, or each agent administered in separate oral dosage
formulations. Where separate dosage formulations are used, a
compound of the present invention and one or more additional active
agents can be administered at essentially the same time, i.e.,
concurrently, or at separately staggered times, i.e., sequentially.
Combination therapy is understood to include all these
regimens.
[0569] An example of combination therapeutic or prophylactic
treatment of atherosclerosis may be wherein a compound of the
present invention or a salt thereof is administered in combination
with one or more of the following active agents: antihyperlipidemic
agents; plasma HDL-raising agents; antihypercholesterolemic agents,
fibrates, vitamins, aspirin, and the like. As noted above, the
compounds of the present invention can be administered in
combination with more than one additional active agent.
[0570] Another example of combination therapy can be seen in
treating (therapeutically or prophylactically) diabetes and related
disorders wherein the compounds of the present invention and salts
thereof can be effectively used in combination with, for example,
sulfonylureas, biguanides, thiazolidinediones, .alpha.-glucosidase
inhibitors, other insulin secretogogues, insulin as well as the
active agents discussed above for treating atherosclerosis.
[0571] Other examples of therapeutic agents which can be used in
combination with the compounds of the present invention include
insulin sensitizers, PPAR.gamma. agonists, glitazones,
troglitizone, pioglitazone, englitazone, MCC-555, BRL 49653,
biguanides, metformin, phenformin, insulin, insulin minetics,
sulfonylureas, tolbutamide, glipizide, alpha-glucosidase
inhibitors, acarbose, cholesterol lowering agent, HMG-CoA reductase
inhibitors, lovastatin, simvastatin, pravastatin, fluvastatin,
atrovastatin, rivastatin, other statins, sequestrants,
cholestyramine, colestipol, dialkylaminoalkyl derivatives of a
cross-linked dextran, nicotinyl alcohol, nicotinic acid, a
nicotinic acid salt, PPAR.alpha. agonists, fenofibric acid
derivatives, gemfibrozil, clofibrate, fenofibrate, benzafibrate,
inhibitors of cholesterol absorption, beta-sitosterol, acyl
CoA:cholesterol acyltransferase inhibitors, melinamide, probucol,
PPAR.delta. agonists, antiobesity compounds, fenfluramine,
dexfenfluramine, phentiramine, sulbitramine, orlistat, neuropeptide
Y5 inhibitors, .beta..sub.3 adrenergic receptor agonists, and ileal
bile acid transporter inhibitors.
[0572] An effective amount of a compound of the present invention
can be used for the preparation of a medicament useful for treating
(therapeutic and prophylactic) hyperglycemia, dyslipidemia, Type II
diabetes, Type I diabetes, hypertriglyceridemia, syndrome X,
insulin resistance, heart failure, diabetic dyslipidemia,
hyperlipidemia, hypercholesteremia, hypertension, obesity, anorexia
bulimia, polycystic ovarian syndrome, anorexia nervosa,
cardiovascular disease (especially atherosclerosis), lowering
tryglyceride levels, raising the plasma level of high density
lipoprotein or other diseases where insulin resistance is a
component or other diosorders mediated by a PPAR receptor. Included
is treating, preventing or reducing the risk of developing
atherosclerosis, and for preventing or reducing the risk of having
a first or subsequent atherosclerotic disease event in mammals,
particularly in humans. In general an effective amount of a
compound of the present invention (1) reduces serum glucose levels
of a patient, or more specifically HbA1c, typically by about 0.7%;
(2) reduces the serum triglyceride levels of a patient, typically
by about 20%; and/or (3) increases the serum HDL levels in a
patient, preferably about 30%.
[0573] Additionally, an effective amount of a compound of the
present invention and an effective amount of one or more of the
active agents listed above can be used together for the preparation
of a medicament useful for the above-described treatments.
[0574] Preferably compounds of the invention or pharmaceutical
formulations containing these compounds are in unit dosage form for
administration to a mammal. The unit dosage form can be any unit
dosage form known in the art including, for example, a capsule, an
IV bag, a tablet, or a vial. The quantity of active ingredient
(viz., a compound of the present invention or salts thereof) in a
unit dose of composition is a therapeutically effective amount and
may be varied according to the particular treatment involved. It
may be appreciated that it may be necessary to make routine
variations to the dosage depending on the age and condition of the
patient. The dosage will also depend on the route of administration
that may be by a variety of routes including oral, aerosol, rectal,
transdermal, subcutaneous, intravenous, intramuscular,
intraperitoneal and intranasal.
[0575] Pharmaceutical formulations of the invention are prepared by
combining (e.g., mixing) an effective amount of a compound of the
invention together with a pharmaceutically acceptable carrier or
diluent. The present pharmaceutical formulations are prepared by
known procedures using well-known and readily available
ingredients.
[0576] In making the compositions of the present invention, the
active ingredient will usually be admixed with a carrier, or
diluted by a carrier, or enclosed within a carrier that may be in
the form of a capsule, sachet, paper or other container. When the
carrier serves as a diluent, it may be a solid, lyophilized solid
or paste, semi-solid, or liquid material which acts as a vehicle,
or can be in the form of tablets, pills, powders, lozenges,
elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a
solid or in a liquid medium), or ointment, containing, for example,
up to 10% by weight of the active compound. The compounds of the
present invention are preferably formulated prior to
administration.
[0577] For the pharmaceutical formulations any suitable carrier
known in the art can be used. In such a formulation, the carrier
may be a solid, liquid, or mixture of a solid and a liquid. For
example, for intravenous injection the compounds of the invention
may be dissolved in at a concentration of about 0.05 to about 5.0
mg/ml in a 4% dextrose/0.5% Na citrate aqueous solution.
[0578] Solid form formulations include powders, tablets and
capsules. A solid carrier can be one or more substance that may
also act as flavoring agents, lubricants, solubilisers, suspending
agents, binders, tablet disintegrating agents and encapsulating
material.
[0579] Tablets for oral administration may contain suitable
excipients such as calcium carbonate, sodium carbonate, lactose,
calcium phosphate, together with disintegrating agents, such as
maize, starch, or alginic acid, and/or binding agents, for example,
gelatin or ac acia, and lubricating agents such as magnesium
stearate, stearic acid, or talc.
[0580] In powders the carrier is a finely divided solid that is in
admixture with the finely divided active ingredient. In tablets the
active ingredient is mixed with a carrier having the necessary
binding properties in suitable proportions and compacted in the
shape and size desired.
[0581] Advantageously, compositions containing the compound of the
present invention or the salts thereof may be provided in dosage
unit form, preferably each dosage unit containing from about 1 to
about 500 mg be administered although it will, of course, readily
be understood that the amount of the compound or compounds of the
present invention actually to be administered will be determined by
a physician, in the light of all the relevant circumstances.
[0582] Powders and tablets preferably contain from about 1 to about
99 weight percent of the active ingredient that is the novel
compound of this invention. Suitable solid carriers are magnesium
carbonate, magnesium stearate, talc, sugar, lactose, pectin,
dextrin, starch, gelatin, tragacanth, methyl cellulose, sodium
carboxymethyl cellulose, low melting waxes, and cocoa butter.
[0583] The following pharmaceutical formulations 1 through 8 are
illustrative only and are not intended to limit the scope of the
invention in any way. "Active Ingredient", refers to a compound
according to the present invention or salts thereof.
Formulation 1
[0584] Hard gelatin capsules are prepared using the following
ingredients:
1 Quantity (mg/capsule) Active Ingredient 250 Starch, dried 200
Magnesium stearate 10 Total 460 mg
Formulation 2
[0585] A tablet is prepared using the ingredients below:
2 Quantity (mg/tablet) Active Ingredient 250 Cellulose,
microcrystalline 400 Silicon dioxide, fumed 10 Stearic acid 5 Total
665 mg
[0586] The components are blended and compressed to form tablets
each weighing 665 mg
Formulation 3
[0587] An aerosol solution is prepared containing the following
components:
3 Weight Active Ingredient 0.25 Ethanol 25.75 Propellant 22
(Chlorodifluoromethane) 74.00 Total 100.00
[0588] The Active Ingredient is mixed with ethanol and the mixture
added to a portion of the propellant 22, cooled to 30.degree. C.
and transferred to a filling device. The required amount is then
fed to a stainless steel container and diluted with the remainder
of the propellant. The valve units are then fitted to the
container.
Formulation 4
[0589] Tablets, each containing 60 mg of Active ingredient, are
made as follows:
4 Active Ingredient 60 mg Starch 45 mg Microcrystalline cellulose
35 mg Polyvinylpyrrolidone (as 10% solution in water) 4 mg Sodium
carboxymethyl starch 4.5 mg Magnesium stearate 0.5 mg Talc 1 mg
Total 150 mg
[0590] The Active Ingredient, starch and cellulose are passed
through a No. 45 mesh U.S. sieve and mixed thoroughly. The aqueous
solution containing polyvinylpyrrolidone is mixed with the
resultant powder, and the mixture then is passed through a No. 14
mesh U.S. sieve. The granules so produced are dried at 50.degree.
C. and passed through a No. 18 mesh U.S. sieve. The sodium
carboxymethyl starch, magnesium stearate and talc, previously
passed through a No. 60 mesh U.S. sieve, are then added to the
granules which, after mixing, are compressed on a tablet machine to
yield tablets each weighing 150 mg.
Formulation 5
[0591] Capsules, each containing 80 mg of Active Ingredient, are
made as follows:
5 Active Ingredient 80 mg Starch 59 mg Microcrystalline cellulose
59 mg Magnesium stearate 2 mg Total 200 mg
[0592] The Active Ingredient, cellulose, starch, and magnesium
stearate are blended, passed through a No. 45 mesh U.S. sieve, and
filled into hard gelatin capsules in 200 mg quantities.
Formulation 6
[0593] Suppositories, each containing 225 mg of Active Ingredient,
are made as follows:
6 Active Ingredient 225 mg Saturated fatty acid glycerides 2,000 mg
Total 2,225 mg
[0594] The Active Ingredient is passed through a No. 60 mesh U.S.
sieve and suspended in the saturated fatty acid glycerides
previously melted using the minimum heat necessary. The mixture is
then poured into a suppository mold of nominal 2 g capacity and
allowed to cool.
Formulation 7
[0595] Suspensions, each containing 50 mg of Active Ingredient per
5 ml dose, are made as follows:
7 Active Ingredient 50 mg Sodium carboxymethyl cellulose 50 mg
Syrup 1.25 ml Benzoic acid solution 0.10 ml Flavor q.v. Color q.v.
Purified water to total 5 ml
[0596] The Active Ingredient is passed through a No. 45 mesh U.S.
sieve and mixed with the sodium carboxymethyl cellulose and syrup
to form a smooth paste. The benzoic acid solution, flavor and color
are diluted with a portion of the water and added, with stirring.
Sufficient water is then added to produce the required volume.
Formulation 8
[0597] An intravenous formulation maybe prepared as follows:
8 Active Ingredient 100 mg Isotonic saline 1,000 ml
[0598] The solution of the above materials generally is
administered intravenously to a subject at a rate of 1 ml per
minute.
[0599] The compounds of the present invention, in general, may be
prepared according to the Reaction Schemes described below. When
describing various aspects of the present compounds, the terms
"Tail", "Linker" and "Head" are used as their concept is
illustrated below in General Reaction Scheme. 21
[0600] As shown in General Reaction Scheme, the compounds of the
present invention can be divided into three regions designated as
Tail, Linker and Head. By a retrosynthetic analysis, key bond
disconnections occur between each of these 3 regions. According to
route A, a nucleophilic tailpiece is coupled to an electrophilic
compound linker-headpiece, which in turn is derived by coupling the
linker region with the headpiece by route B. Alternately according
to route C, the headpiece can be coupled to the compound
tailpiece-linker, derived by coupling the nucleophilic tailpiece
with the electophilic linker by route D. The following reaction
schemes illustrate more detailed synthetic routes to prepare the
compounds of the present invention. 22
[0601] Reaction Scheme A shows the preparation of a general
headpiece of the present compounds. Condensation of an aromatic
aldehyde (1) with an alpha-alkoxyacetic acid ester (2) in the
presence of a suitable base, such as lithium
bis(trimethylsilyl)amide yields hydroxyester (3). The free hydroxyl
group is converted into a leaving group by treatment with either
methanesulfonyl chloride or trifluoroacetic anhydride. When the
aromatic alcohol is protected as a benzyl ether (Pg is PhCH.sub.2),
exhaustive hydrogenolysis using hydrogen over Pd/C yields compound
(5). Ester hydrolysis of (5) using aqueous hydroxide solution
affords acid compound (6), which can be resolved into the
corresponding enantiomers by using an appropriate chiral amine,
such as (-)-cinchonidine. The acid (7) can be esterified using the
appropriate alcohol under acidic conditions, such as ethanol and
sulfuric acid, or an alkyl halide under basic conditions, such as
cesium carbonate in DMF to give compound (8). 23
[0602] An alternate route to the headpiece is shown in Reaction
Scheme B. The ketone function of ketoacid (9) is subjected to a
reducing agent, such as B-chloro-diisopinocamphenylborane, to give
hydroxyacid (10). The phenolic hydroxyl group is then protected
with the protecting group to give compound (11). The compound (11)
reacted with a dimethyl ketal followed by phenol ether cleavage
gives an dioxolanone intermediate, which affords a 2-alkoxyacid
upon treatment with a suitable Lewis acid, such as TiCl.sub.4 and a
reducing reagent, such as a trialkylsilane. Esterification yields
2-alkoxyester (12). Alternatively, acid (11) can be esterified to
yield ester (13), which can be treated with an electrophile such as
an alkyl halide, and an additive such as NaH or silver (I) oxide to
afford ether compound (14). 24
[0603] As shown in Reaction Scheme C, a Claisen rearrangement can
be used to alkylate the headpiece. Aryl alcohol (15) is treated
with an alkyl bromide in the presence of a suitable base, such as
NaH to give alkyl ether (16). Heating the ether compound (16) in
dimethylaniline affords the alkylated headpiece compound (17).
25
[0604] As shown in Reaction Scheme D, halogen substitution can be
introduced into the headpiece by treating aryl alcohol (18) with an
N-halosuccinimide in organic solvent to yield the compound (19).
The compound (19) then undergoes a coupling reaction in the
presence of palladium catalyst to yield the corresponding aryl and
styrenyl compounds (20). 26
[0605] Reaction Scheme E illustrates a synthesis of the present
compounds by the general linker-headpiece route (General Scheme,
routes A and B). The headpiece compoud (21) is coupled with a
suitably monoprotected diol using a trialkylphosphine or
triarylphosphine and an azodicarboxylate derivative (Mitsunobu
conditions) to yield aryl ether (22). Deprotection of the alcohol
function in the linker affords the compound (23), which then
undergoes Mitsunobu coupling reaction with a tailpiece aryl alcohol
(ArOH) to give compound (24). Further ester hydrolysis affords acid
compound (25). Alternatively, the alcohol compound (23) can be
converted to the corresponding halide (26) using a carbon
tetrahalide and triphenylphosphine. Treatment of compound (26) with
a tailpiece aryl alcohol (ArOH) in the presence of a suitable base,
such as cesium carbonate affords compound (24), which then
undergoes hydrolysis to give acid compound (25). 27
[0606] As shown in Reaction Scheme F, the compounds of the present
invention can be prepared by the general tailpiece-linker to
headpiece route (General Scheme, route C). The headpiece compound
of alcohol (27) is treated with a tailpiece-inker halide (ArO-L-X)
in the presence of a suitable base, such as potassium or cesium
carbonate to afford the compound (28), which then undergoes ester
hydrolysis to yield acid compound (29). 28
[0607] As shown in Reaction Scheme G, the headpiece can be attached
to a resin allowing for a solid phase synthesis of the target
compounds. Carboxylic acid (30) is attached to a suitable resin,
such as the Wang resin, using an appropriate coupling reagent, such
as diisopropyl carbodiimide (DIPC). Cleavage of the aryl alcohol
protecting group, such as a tert-butyldimethylsilyl ether
(t-BuMe.sub.2Si) with the appropriate reagent, such as
tetra-n-butylammonium fluoride gives aryl alcohol (32). The tail
and linker regions are introduced as described in Reaction Schemes
E and F to produce the compound (33). The carboxylic acid (34) can
be released from the resin under suitable conditions, such as
trifluoroacetic acid. 29
[0608] Reaction Scheme H illustrates a synthetic route to prepare
the compounds of the present invention having alkynyl linkers. The
headpiece compound (35) can be converted to the corresponding aryl
triflate (36) (or aryl iodide) using phenyl triflamide and an
appropriate base, such as NaH. The palladium catalyzed coupling
reaction of compound (36) with an alkynyl alcohol gives the
linker-headpiece intermediate (37). Coupling of compound (37) with
various tailpiece alcohols can be achieved as described in Reaction
Scheme E to afford the compound (38), which then undergoes a
hydrolysis to yield the acid compound (40). 30
[0609] Alternative to Reaction Scheme H, the headpiece compound of
triflate (41) can be combined with a tailpiece-linker to give the
coupled compound (42) in one step as shown in Reaction Scheme I.
The compound (42) then undergoes a hydrolysis to give the acid
compound (43). 31
[0610] As shown in Reaction Scheme 3, the headpiece compound of
triflate (44) can be coupled with trimethylsilylacetylene using
palladium catalysis to give the acetylenic headpiece (45) after
fluoride mediated cleavage of the silyl group. The alkyne (45) is
hydrolyzed under aqueous acidic conditions to the methyl ketone,
which is then brominated with a suitable agent, such as copper (I)
bromide to give bromoketone (46). Treatment of the compound (46)
with a tailpiece aryl alcohol in the presence of a suitable base,
such as potassium carbonate and aqueous base hydrolysis affords the
acid compound (47). 32
[0611] As shown in Reaction Scheme K, an alkyne function in the
linker region of the present compounds can be modified. The alkyne
can be oxidized to ketone to give compound (49) by using an
appropriate oxidizing agent, such as mercuric oxide. The ketone can
be further modified to the corresponding oximes (51) by treatment
with an alkoxyamine followed by hydrolysis. Alternatively, the
alkynyl function can be reduced to the alkylene as in compound (50)
by using an appropriate reducing agent, such as hydrogen over
palladium-on-carbon. 33
[0612] Reaction Scheme L illustrates various synthetic routes to
the linker region. In route (a), 1,3-propane diol (52) is converted
to the cyclic sulfonate ester (53) upon treatment with thionyl
chloride followed by appropriate oxidation reagents, such as
ruthenium trichloride and sodium periodate. Ring opening of the
intermediate (53) is effected upon treatment with a tailpiece
alcohol and a suitable base such as potassium tert-butoxide,
followed by an acidic workup procedure to give the linker alcohol
compound (54). The alcohol is then converted to the halide by using
an appropriate reagent, such as a carbontetrahalide and a
triarylphosphine to afford the compound (55). In route (b), the
compound of dibromo-linker (56) is reacted with approximately one
mole equivalent of the tailpiece aryl alcohol in the presence of a
suitable base, such as potassium carbonate to give the bromo-ether
compound (57).
[0613] In route (c), the compound of diol-linker (58) is coupled
with approximately one mole equivalent of the tailpiece alcohol
under Mitsunobu reaction conditions to give the hydroxy-ether
compound (59).
[0614] In route (d), 1,3-propane diol (60) is converted to the
halide (61), which is then reacted with the headpiece aryl alcohol
under the Mitsunobu reaction condition to give the bromo-ether
compound (62). 3435
[0615] Reaction Scheme M illustrates the synthetic routes to
compounds with aryl-containing linkers. In route (a), The compound
of headpiece triflate (60) is coupled with an arylboronic acid in
the presence of palladium catalyst. Reduction of the intermediate
aldehyde using a suitable reagent such as sodium borohydride,
affords the arylic alcohol compound (61). The compound (61) can be
coupled with the tailpiece aryl alcohol (ArOH) under Mitsunobu
conditions followed by ester hydrolysis to give the acid compound
(62).
[0616] In route (b), the headpiece alcohol (63) is coupled with
approximately one mole equivalent of aryl dibromide in the presence
of palladium catalyst to give aryl bromide (64). The compound (64)
is then coupled similarly to the tailpiece aryl alcohol (ArOH)
followed by ester hydrolysis to afford the acid compound (65).
36
[0617] Reaction Scheme N shows a synthetic route to modify the
tailpiece region of the present compounds. The compound of
para-fluorobenzophenone (66) is treated with a suitable nucleophile
such as secondary amines and alkoxides, and then subjected to ester
hydrolysis to give the acid compound (67).
[0618] The carbonyl function of benzophenone (68) can be reduced by
using an appropriate reagent, such as hydrogen over
palladium-on-carbon to yield the corresponding alcohol (69) after
ester hydrolysis. The ketone moiety of compound (68) can be also
modified to the corresponding oximes (70) by treatment with an
alkoxyamine followed by hydrolysis. 37
[0619] Reaction Scheme O shows the synthetic routes to prepare the
tailpiece region of the compounds. A Claisen rearrangement is used
to alkylate the tailpiece aryl ring as shown in route (a). Aryl
alcohol (71) is treated with an alkyl bromide in the presence of a
suitable base, such as NaH to give alkyl ether (72). Heating this
ether in dimethylaniline gives the alkylated headpiece (73).
[0620] Solid phase methods to synthesize the tailpiece are
described in route (b). Aryl alcohol is coupled to a suitable
resin, such as the Wang resin under Mitsunobu conditions. Coupling
the resin with a nitro aryl alcohol gives an intermediate that is
reduced under-appropriate conditions, such as tin (II) chloride in
DMF to give aniline (74). The nitrogen function is reacted further
with suitable reagents, such as isocyanates, acid chlorides or
chloroformates to give the corresponding ureas, carbamates and
amides, respectively. Cleavage from the resin under acidic
conditions, such as trifluoroacetic acid in dichloromethane affords
the amino substituted tailpiece of aryl alcohol compound (75).
[0621] Alternatively, coupling the resin with an iodo aryl alcohol
gives iodide intermediate (76). The aryl iodide (76) then can be
coupled directly with aryl boronic acids under palladium catalysis
to give biaryl tailpiece aryl alcohols (77) upon cleavage from the
resin under acidic condition. Iodide intermediate (76) can also be
converted to the trialkylstannane (78) in the presence of palladium
catalyst. Subsequent palladium catalyzed coupling with suitable
reagents, such as acid chloride and upon cleavage from the resin
under acidic condition afford the carbonyl substituted tailpiece
aryl alcohol compound (79).
[0622] Exemplification
[0623] Instrumental Analysis
[0624] .sup.1H NMR spectra were recorded on Varian 400 MHz, Bruker
200, 300 or 500 MHz spectromethers at ambient temperature. Data are
reported as follows: chemical shift in ppm from internal standard
tetramethylsilane on the .delta. scale, multiplicity (b=broad,
s=singlet, d=doublet, t=triplet, q=quartet, qn=quintet and
m=multiplet), integration, and coupling constant (Hz). .sup.13C NMR
were recorded on a Bruker 200, 300 or 500 MHz spectromether at
ambient temperature. Chemical shifts are reported in ppm from
tetramethylsilane on the .delta. scale, with the solvent resonance
employed as the internal standard (CDCl.sub.3 at 77.0 ppm and
DMSO-d.sub.6 at 39.5 ppm). High resolution mass spectra were
obtained on VG ZAB 3F or VG 70 SE spectromethers. Analytical thin
layer chromatography was performed on EM Reagent 0.25 mm silica gel
60-F plates. Visualization was accomplished with UV light
[0625] Standard Synthesis Procedures
[0626] Certain standard synthesis procedures were used in preparing
many of the exemplified compounds of the present invention. These
Standard Procedures were:
[0627] Standard Procedure for Mitsounobu coupling hydrolysis
procedure (A): A solution of triphenylphosphine (1.42 mmol) in 10
mL of dry THF was treated at 0.degree. C. with
diethylazodicarboxylate (1.42 mmol) and stirred for 20 min A
solution of (2S)-3-[4-(3-Hydroxy-prop-1-ynyl)-phenyl-
]-2-methoxy-propionic acid ethyl ester (1.19 mmol) and
4-phenylphenol (1.42 mmol) in 5 mL of dry THF was added to the
solution, and the mixture stirred at room temperature overnight.
The mixture was concentrated to dryness under vacuum and purified
by silica gel chromatography (silica gel, hexanes ethyl acetate
10:1 to 3:1). Fractions with Rfs 0.5 and 0.42 (hexanes/ethyl
acetate 2:1) corresponding to the couple compound and starting
phenol, respectively, were combined and concentrated to dryness.
The mixture was dissolved in 4 mL of 1N NaOH and 12 mL of methanol
and stirred at room temperature until TLC indicated the
disappearance of starting material. The methanol was removed under
vacuum, and the aqueous solution was diluted with 20 mL of brine
and washed with diethyl ether (3.times.15 mL). The aqueous phase
was acidified with 1N HCl (pH 1-2) and extracted with ethyl acetate
(3.times.15 mL). The organic layer dried (MgSO.sub.4) and
concentrated under vacuum.
[0628] Standard Procedure for the Mitsounobu coupling procedure
(B): A solution of triphenylphosphine (1.42 mmol) in 10 mL toluene
or THF was treated at 0.degree. C. with DEAD or DIAD (1.42 mmol)
and stirred for 20 min. A solution of
(2S)-3-(4-Hydroxy-phenyl)-2-methoxy-propionic acid ethyl ester
(1.19 mmol) and the corresponding alcohol (1.42 mmol) in 5 mL of
toluene or THF was added to the solution, and the mixture stirred
at room temperature overnight. The mixture was concentrated to
dryness under-vacuum and purified by silica gel chromatography
[0629] Standard hydrolysis Procedure (C):
(2S)-3-{4-[4-(Biphenyl-4-yloxy)--
but-1-ynyl]-phenyl}-2-methoxy-propionic acid ethyl ester (0.5 g,
1.17 mmol) was dissolved in 20 mL of 1N NaOH (or LiOH) and 60 mL of
methanol and was stirred at room temperature until TLC indicated
the disappearance of starting material (ca. 3 h). The methanol was
removed under vacuum, and the aqueous solution diluted with 20 mL
of brine and washed with diethyl ether (3.times.60 mL). The aqueous
phase was acidified with 1N HCl (until pH 1-2) and extracted with
ethyl acetate (3.times.60 mL). The organic layer dried (MgSO.sub.4)
and concentrated under vacuum.
[0630] Standard Procedure for Monoprotection of diols (D): A
solution of the corresponding diol (1 eq) in dry THF was cooled to
0.degree. C. Sodium hydride (1 eq) was added, and the mixture
reaction was stirred 30 min at that temperature.
Tert-butyldimethylsilyl chloride (0.95 eq) was added, and the
mixture was stirred at room temperature overnight. Then a 10%
Na.sub.2CO.sub.3 solution was added and the mixture was extracted
with ethyl acetate. The combined organic layers were washed with
brine; dried (MgSO.sub.4) and concentrated in vacuo. The residue
was purified by silica gel chromatography.
[0631] Standard Procedure for the cleveage of the protected
alcohols (E): A mixture solution of the corresponding protected
alcohol in THF was treated with tetrabutylamonium fluoride (1M in
THF) (2 eq). The solution was stirred at room temperature until
reaction is completed by TLC, then quenched with water and
extracted with Ethyl Acetate to give a crude product which was
purified by silica gel chromatography.
[0632] Standard Procedure (F): The reaction was carried out in a
polypropylene syringe equipped with a polypropylene frit. A
suspension of the resin-linked phenol (1 eq) was suspended in THF
(0.02 M). A solution of 1,3-propanediol (5 eq) in THF was added
followed by a mixture of triphenylphosphine (5 eq) and
diisopropylazo-dicarboxylate (5 eq) in THF. The mixture was shaken
at room temperature overnight. The reaction solvent was removed,
and the resin was washed sequentially with THF (2.times.),
CH.sub.2Cl.sub.2 (2.times.), DMF (2.times.), CH.sub.2Cl.sub.2
(2.times.), methanol and CH.sub.2Cl.sub.2 (3.times.). The resultant
polymer was dried under vacuum overnight to produce the targeted
immobilized alcohol.
[0633] Standard Procedure (G): The reaction was carried out in a
polypropylene syringe equipped with a polypropylene frit. A
suspension of the resin-linked alcohol (1 eq) was suspended in a
mixture 1:1 THF/CH.sub.2Cl.sub.2 (0.015 K. A solution of phenol (10
eq) dissolved in a mixture of 1:1 THF/CH.sub.2Cl.sub.2 was added
followed by a mixture of triphenylphosphine (5 eq) and
diisopropylazo-dicarboxylate (5 eq) in THF/CH.sub.2Cl.sub.2 1:1.
The mixture was shaken at room temperature overnight, and the
reaction solvent was removed. The resin was washed sequentially
with 1:1 THF/CH.sub.2Cl.sub.2 (2.times.), THF (2.times.),
CH.sub.2Cl.sub.2 (2.times.), DMF (2.times.), CH.sub.2Cl.sub.2
(2.times.), methanol, and CH.sub.2Cl.sub.2 (2.times.). The resin
was dried under vacuum for 5 h and treated with 50% TFA in
CH.sub.2Cl.sub.2. The solution was filtered and concentrated, and
the residue was purified by HPLC-MS chromatography to produce the
desired product.
[0634] Standard Procedure (H): Lithium hydroxide 1N solution in
water (0.245 mL) was added to a solution of the ester (0.073 mmol)
in tetrahydrofuran (1 mL) at room temperature. The reaction mixture
was stirred at room temperature for 1.5 hours, diluted with water
(10 mL) and extracted with diethyl ether (3.times.10 mL). The
aqueous layer was acidified with 1N HCl to pH 1 and extracted with
Diethyl ether (5.times.15 mL). The combined organic layers were
dried (MgSO.sub.4), filtered and concentrated under vacuum to
produce the corresponding acid.
[0635] Standard Procedure (I): A mixture of the corresponding
phenol (1 eq) and the bromoalkyl derivative (1 eq) with
K.sub.2CO.sub.3 (3 eq) were refluxed in acetonitrile overnight.
Cooled the mixture reaction and concentrated to dryness to give a
crude which was purified by chromatography in silica gel to give
the product.
[0636] Standard Procedure (J). A mixture of the corresponding
phenol (1.5 eq), and the bromoalkyl derivative (1 eq) in DMF were
treated with Cs.sub.2CO.sub.3 (3 eq). The mixture reaction was
stirred at room temperature overnight and then filtered. Removed
the DMF under vacuo and added methanol to the residue treating the
mixture with NaOH 1M (10 eq) and stirred for 3 h. The solvent was
evaporated and the salts were dissolved in water. The aqueous phase
was acidified to pH 2 and extracted with dichloromethane, filtered
through a hydrophobic syringe and the organic layer purified by
HPLC-MS.
EXAMPLE 1
[0637]
(2S)-3-{4-[3-(Biphenyl-4-yloxy)-prop-1-ynyl]-phenyl}-2-methoxy-prop-
ionic acid 38
[0638] Step A
[0639]
(2S)-2-Methoxy-3-(4-trifluoromethanesulfoxy-phenyl)-propionic acid
ethyl ester 39
[0640] To a solution of (S)-2-methoxy-3-hydroxyphenyl-propionic
acid ethyl ester (0.388 g, 1.73 mmol) in 40 mL of dry THF cooled to
-20.degree. C. was added sodium hydride (0.073 g, 1.82 mmol, 60%
oil dispersion). The mixture was stirred at -20.degree. C. for 30
min. Phenyl triflimide (0.68 g, 1.90 mmol) was added in one
portion, and the solution was stirred at room temperature overnight
and concentrated to dryness under vacuum. The residue was
partitioned between water (20 mL) and diethyl ether (20 mL). The
layers were separated, and the aqueous solution was extracted with
diethyl ether (2.times.20 ml). The combined organic layers were
washed with 10% Na.sub.2CO.sub.3 (6.times.20 mL) and brine (20 mL),
dried (MgSO.sub.4), and concentrated to a yellow oil (574 mg, 97%).
.sup.1H-NMR (200.15 MHz, CDCl.sub.3): .delta. 7.34-7.16 (m, 4H),
4.18 (q, 2H, J=7.0), 3.93 (dd, 1H, J=7.3, 5.6), 3.36 (s, 3H), 3.05
(s, 1H), 3.02 (d, 1H, J=2.4 Hz), 1.22 (t, 3H, J=7.25).
[0641] Step B
[0642]
(2S)-3-[4-(3-Hydroxy-prop-1-ynyl)-phenyl]-2-methoxy-propionic acid
ethyl ester 40
[0643] A solution of
(2S)-2-methoxy-3-(4-trifluoromethane-sulfonyloxy-phen-
yl)-propionic acid ethyl ester (0.861 g, 2.53 mmol), propargyl
alcohol (0.88 mL, 15.18 mmol), triethylamine (1.41 mL, 10.12 mmol)
and dichlorobis(triphenylphosphine)palladium (II) in 10 mL of dry
DMF was heated to 90.degree. C. for 2 hours. The reaction mixture
was cooled to room temperature, diluted with 50 mL of water, and
extracted with diethyl ether (3.times.30 mL). The combined organic
layers were washed with 0.5 N HCl (2.times.20 mL) and brine (20
mL), dried (MgSO.sub.4), and concentrated. The residue purified by
column chromatography (silica gel, hexanes/ethyl acetate 2:1,
R.sub.f0.17) to give a yellow-brown oil (0.211 g, 32%). .sup.1H-NMR
(200.15 MHz, CDCl.sub.3): .delta. 7.35 (d, 2H, J=8.1), 7.18 (d, 2H,
J=8.1), 4.48 (s, 2H), 4.17 (q, 2H, J=7.3), 3.93 (dd, 1H, J=7.3,
5.7), 3.34 (s, 3H), 3.02 (s, 1H), 2.99 (d, 1H, J=2.2), 1.8 (s, 1H),
1.22 (t, 3H, J=7.3).
[0644] Step C
[0645]
(2S)-3-{4-[3-(Biphenyl-4-yloxy)-prop-1-ynyl]-phenyl}-2-methoxy-prop-
ionic acid
[0646] The title compound was prepared from
(2S)-3-[4-(3-hydroxy-prop-1-yn- yl)-phenyl]-2-methoxy-propionic
acid ethyl ester using the standard Mitsunobu coupling-hydrolysis
procedure (Standard Procedure A) to produce a white solid. Mp
111-112.degree. C. .sup.1H-NMR (200.15 MHz, CDCl.sub.3): .delta.
7.58-7.52 (m, 4H), 7.45-7.30 (m, 5H), 7.19 (d, 1H, J=8.3), 7.10
(dd, 3H, J=6.7, 1.9), 4.94 (s, 2H), 3.98 (dd, 1H, J=7.5, 4.3); 3.37
(s, 3H), 3.13 (dd, 1H, J=14.5, 4.6), 2.99 (dd, 1H, J=14.2, 7.8). MS
(ES) for C.sub.25H.sub.22O.sub.4 [M+NH.sub.4].sup.+: 404,
[M+Na].sup.+:409.
EXAMPLE 2
[0647]
(2S)-3-{4-[3-(4-Benzoyl-phenoxy)-prop-1-ynyl]-phenyl}-2-methoxy-pro-
pionic acid: 41
[0648] The title compound was prepared from
(2S)-3-[4-(3-hydroxy-prop-1-yn- yl)-phenyl]-2-methoxy-propionic
acid ethyl ester (from Example 1, Step B) via the standard
Mitsunobu coupling-hydrolysis procedure (Standard Procedure A) to
produce a white oily solid. .sup.1H-NMR (200.15 MHz, CDCl.sub.3):
.delta. 7.84-7.71 (m, 4H), 7.55-7.33 (m, 5H), 7.17 (d, 2H, J=8.0),
7.07 (d, 2H, J=8.8), 4.96 (s, 2H), 3.96 (dd, 1H, J=7.7, 4.4), 3.35
(s, 3H), 3.11 (dd, 1H, J=14.3, 4.4), 2.97 (dd, 1H, J=14.3,
7.3).
EXAMPLE 3
[0649]
(2S)-2-Methoxy-3-{4-[3-(4-phenoxy-phenoxy)-prop-1-ynyl]-phenyl}-pro-
pionic acid: 42
[0650] The title compound was prepared from
(2S)-3-[4-(3-Hydroxy-prop-1-yn- yl)-phenyl]-2-methoxy-propionic
acid ethyl ester via (from Example 1, Step B) the standard
Mitsunobu coupling-hydrolysis procedure (Standard Procedure A) to
produce a white oily solid (41%). .sup.1H-NMR (200.15 MHz,
CDCl.sub.3): .delta. 7.38-7.15 (m, 5H), 7.02-6.76 (m, 8H); 4.86 (s,
2H), 3.98 (dd, 1H, J=7.3, 4.4), 3.36 (s, 3H), 3.12 (dd, 1H, J=14.3,
4.4), 2.98 (dd, 1H, J=14.3, 7.3). MS (ES) for
C.sub.25H.sub.22O.sub.5 [M+NH.sub.4].sup.+: 420.2, [M+Na].sup.+:
425.2.
EXAMPLE 4
[0651]
(2S)-3-{4-[3-(4-Fluoro-phenoxy)-prop-1-ynyl]-phenyl}-2-methoxy-prop-
ionic acid 43
[0652] The title compound was prepared from
(2S)-3-[4-(3-Hydroxy-prop-1-yn- yl)-phenyl]-2-methoxy-propionic
acid ethyl ester (from Example 1, Step B) via the standard
Mitsunobu coupling-hydrolysis procedure (Standard Procedure A) to
produce a white solid of the title compound. .sup.1H-NMR
(CDCl.sub.3, 200.15 MHz): .delta. 7.34 (d, J=8.1 Hz, 2H); 7.16 (d,
J=8.0 Hz, 2H); 6.98-6.86 (m, 4H); 4.84 (s, 2H); 3.97 (dd, J=7.7,
4.4 Hz, 1H); 3.36 (s, 3H); 3.12 (dd, J=14.3, 4.4 Hz, 1H); 2.98 (dd,
J=14.3, 7.3 Hz, 1H). MS (ES) for C.sub.19H.sub.17FO.sub.4
[M+NH.sub.4].sup.+: 346, [M+Na].sup.+: 351.
EXAMPLE 5
[0653]
(2S)-2-Methoxy-3-{4-[3-(3-phenyl-benzofuran-6-yloxy)-prop-1-ynyl]-p-
henyl}-propionic acid 44
[0654] Step A
[0655] (2S)-3-[4-(3-Chloro-prop-1-ynyl)-phenyl]-2-methoxy-propionic
acid ethyl ester 45
[0656] The title compound was prepared from
(2S)-3-[4-(3-hydroxy-prop-1-yn- yl)-phenyl]-2-methoxy-propionic
acid ethyl ester (0.060 g, 0.23 mmol) (from Example 1, Step B) in
dry DMF (5 ml) and treated with triethyl amine (0.69 mmol) and
mesylchloride (0.46 mmol). The mixture reaction was stirred
overnight and the crude product was extracted with H.sub.2O/Ether.
The organic layer was dried and concentrated to give a product that
was purified in silica using Hexane/Ethyl Acetate (5/1) to give the
title compound as an oil (0.020 g, 30% yield). MS (ES) for
C.sub.15H.sub.17ClO.sub.3 [M+H].sup.+: 281.2
[0657] Step B
[0658]
(2S)-2-Methoxy-3-{4-[3-(3-phenyl-benzofuran-6-yloxy)-prop-1-ynyl]-p-
henyl}-propionic acid
[0659] A solution of
(2S)-3-[4-(3-Chloro-prop-1-ynyl)-phenyl]-2-methoxy-pr- opionic acid
ethyl ester from Step A (0.071 mmol, 1 eq) in 0.7 ml of DMF in a
16.times.100 mm tube treated with 3-phenyl-6-hydroxybenzofurane
(0.078 mmol, 1.1 eq) Cesium Carbonate (0.213 mmol 3 eq) and NaI
(0.071 mmol, 1 eq) and stirred at room temperature overnight. The
reactants were filtered and washed with DMF several times. The
solvent was evaporated under vacuo and the residue reconstituted in
a mixture of Ethanol (2 ml) and NaOH (1M) (1 ml) and stirred at
room temperature until reaction is completed by HPLC-MS. Then HCl
(1M) was added (until pH=3) and the solvent were eliminated under
vacuo. The residue was reconstituted in CH.sub.2Cl.sub.2/H.sub.2O
and filtered through a hidrofobic syringer. The organic layer was
separated, concentrated and purified by HPLC-MS to get the title
compound. MS(ES) for C.sub.27H.sub.22O.sub.5 [M+H].sup.+:
427.2.
EXAMPLE 6
[0660]
(2S)-3-{4-[3-(4-Butyl-phenoxy)-prop-1-ynyl]-phenyl}-2-methoxy-propi-
onic acid 46
[0661] The title compound was prepared from
(2S)-3-[4-(3-Chloro-prop-1-yny- l)-phenyl]-2-methoxy-propionic acid
ethyl ester from Example 5, Step A and 4-n-butylphenol in a manner
analogous to that described for Example 5, Step B. MS(ES) for
C.sub.23H.sub.26O.sub.4 [M-H].sup.-: 365.2
EXAMPLE 7
[0662]
(2S)-2-Methoxy-3-(4-{3-[4-(4-trifluoromethyl-phenoxy)-phenoxy]-prop-
-1-ynyl}-phenyl)-propionic acid 47
[0663] The title compound was prepared from
(2S)-3-[4-(3-Chloro-prop-1-yny- l)-phenyl]-2-methoxy-propionic acid
ethyl ester from Example 5 Step A and
4-(4-trifluoromethylPhenoxy)-phenol in a manner analogous to that
described for Example 5, Step B. MS(ES) for
C.sub.26H.sub.21F.sub.3O.sub.- 5 [M-H].sup.-: 469.2
EXAMPLE 8
[0664]
(2S)-2-Methoxy-3-{4-[3-(9-oxo-9H-fluoren-2-yloxy)-prop-1-ynyl]-phen-
yl}-propionic acid 48
[0665] The title compound was prepared from
(2S)-3-[4-(3-Chloro-prop-1-yny- l)-phenyl]-2-methoxy-propionic acid
ethyl ester from Example 5 Step A and 2-hydroxy-9-fluorenone in a
manner analogous to that described for Example 5, Step B. MS(ES)
for C.sub.26H.sub.20O.sub.5 [M-H].sup.-: 411.2
EXAMPLE 9
[0666]
(2S)-2-Methoxy-3-{4-[3-(4-oxo-2-phenyl-4H-chromen-7-yloxy)-prop-1-y-
nyl]-phenyl}-propionic acid 49
[0667] The title compound was prepared from
(2S)-3-[4-(3-Chloro-prop-1-yny- l)-phenyl]-2-methoxy-propionic acid
ethyl ester from Example 5, Step A and 7-hydroxyflavone in a manner
analogous to that described for Example 5, Step B. MS(ES) for
C.sub.28H.sub.22O.sub.6[M+H].sup.+: 455.2.
EXAMPLE 10
[0668]
(2S)-3-(4-{3-[4-(2-Fluoro-benzoyl)-phenoxy]-prop-1-ynyl}-phenyl)-2--
methoxy-propionic acid 50
[0669] The title compound was prepared from
(2S)-3-[4-(3-Chloro-prop-1-yny- l)-phenyl]-2-methoxy-propionic acid
ethyl ester from Example 5, Step A and 2-fluoro-4
hydroxybenzophenone in a manner analogous to that described for
Example 5, Step B. MS(ES) for C.sub.26H.sub.21FO[M+H].sup.+:
433.2.
EXAMPLE 11
[0670]
(2S)-2-Methoxy-3-{4-[3-(3-phenylamino-phenoxy)-prop-1-ynyl]-phenyl}-
-propionic acid 51
[0671] The title compound was prepared from
(2S)-3-[4-(3-Chloro-prop-1-yny- l)-phenyl]-2-methoxy-propionic acid
ethyl ester from Example 5, Step A and 3-hydroxydiphenylamine in a
manner analogous to that described for Example 5, Step B. MS(ES)
for CH.sub.23H.sub.23NO [M+H].sup.+: 402.2.
EXAMPLE 12
[0672]
(2S)-3-(4-{3-[4-(4-Fluoro-benzoyl)-phenoxy]-prop-1-ynyl}-phenyl)-2--
methoxy-propionic acid 52
[0673] The title compound was prepared from
(2S)-3-[4-(3-Chloro-prop-1-yny- l)-phenyl]-2-methoxy-propionic acid
ethyl ester from Example 5, Step A and
4-fluoro-4'-hydroxybenzophenone in a manner analogous to that
described for Example 5, Step B. MS(ES) for
C.sub.26H.sub.21FO[M+H].sup.+: 433.2.
EXAMPLE 13
[0674]
(2S)-2-Methoxy-3-{4-[3-(4-oxo-2-phenyl-4H-chromen-6-yloxy)-prop-1-y-
nyl]-phenyl}-propionic acid 53
[0675] The title compound was prepared from
(2S)-3-[4-(3-Chloro-prop-1-yny- l)-phenyl]-2-methoxy-propionic acid
ethyl ester from Example 5, Step A and 6-hydroxyflavone in a manner
analogous to that described for Example 5, Step B. MS(ES) for
C.sub.28H.sub.22O.sub.6[M+H].sup.+: 455.2.
EXAMPLE 14
[0676]
(2S)-3-(4-{3-[3-(4-Fluor-phenyl)-benzofuran-6-yloxy]-prop-1-ynyl}-p-
henyl}-2-methoxy-propionic acid 54
[0677] The title compound was prepared from
(2S)-3-[4-(3-Chloro-prop-1-yny- l)-phenyl]-2-methoxy-propionic acid
ethyl ester from Example 5, Step A and
6-hydroxy-3-(4-fluorophenyl)benzofurane in a manner analogous to
that described for Example 5, Step B. MS(ES) for
C.sub.27H.sub.21FO.sub.5 [M-H].sup.-: 443.2.
EXAMPLE 15
[0678]
(2S)-2-Methoxy-3-(4-{3-[4-(1-methyl-1-phenyl-ethyl)-phenoxy]-prop-1-
-ynyl}-phenyl)-propionic acid 55
[0679] The title compound was prepared from
(2S)-3-[4-(3-Chloro-prop-1-yny- l)-phenyl]-2-methoxy-propionic acid
ethyl ester from Example 5, Step A and 4-cumylphenol in a manner
analogous to that described for Example 5, Step B. MS(ES) for
C.sub.28H.sub.28O.sub.4[M+NH.sub.4].sup.+:446.2.
EXAMPLE 16
[0680]
(2S)-2-Methoxy-3-{4-[3-(4-phenylacetyl-phenoxy)-prop-1-ynyl]-phenyl-
}-propionic acid 56
[0681] The title compound was prepared from
(2S)-3-[4-(3-Chloro-prop-1-yny- l)-phenyl]-2-methoxy-propionic acid
ethyl ester from Example 5, Step A and benzyl-4-hydroxyphenylketone
in a manner analogous to that described for Exapmle 5, Step B.
MS(ES) for C.sub.27H.sub.24O.sub.5 [M-H].sup.-: 427.2.
EXAMPLE 17
[0682]
(2S)-3-{4-[3-(4-Benzyl-phenoxy)-prop-1-ynyl]-phenyl}-2-methoxy-prop-
ionic acid 57
[0683] The title compound was prepared from
(2S)-3-[4-(3-Chloro-prop-1-yny- l)-phenyl]-2-methoxy-propionic acid
ethyl ester from Example 5, Step A and 4-hydroxydiphenylmethane in
a manner analogous to that described for Example 5, Step B. MS(ES)
for C.sub.26H.sub.24O.sub.4[M-H].sup.-: 399.
EXAMPLE 18
[0684]
(2S)-3-[4-(3-{4-[(2-Fluoro-phenyl)-hydroxyimino-methyl]-phenoxy}-pr-
op-1-ynyl)-phenyl]-2-methoxy-propionic acid 58
[0685]
(2S)-3-(4-{3-[4-(2-Fluoro-benzoyl)-phenoxy]-prop-1-ynyl}-phenyl)-2--
methoxy propionic acid from Example 10, (0.01 mmol, 1 eq) was mixed
with Hydroxylamine chlorydrate (4 eq), pyrydine (10 eq) and Ethanol
(2 ml) and the mixture reaction was stirred overnight. The ethanol
was evaporated under vacuo and HCl 0.5% was added to the residue to
pH=3. Extracted with ethyl acetate and concentrated to give the
title product as a mixture of two oximes. MS(ES) for
C.sub.26H.sub.22FNO.sub.5 [M+H].sup.+: 448.2, [M-H].sup.-:
446.2.
EXAMPLE 19
[0686]
(2S)-3-(4-{3-[4-(Hydroxyimino-phenyl-methyl)-phenoxy]-prop-1-ynyl}--
phenyl)-2-methoxy-propionic acid 59
[0687]
(2S)-3-{4-[3-(4-Benzoyl-phenoxy)-prop-1-ynyl]-phenyl}-2-methoxy-pro-
pionic acid (0.01 mmol, 1 eq) (Example 2) was mixed with
Hydroxylamine chlorydrate (4 eq), pyrydine (10 eq) and Ethanol (2
ml) and the mixture reaction was stirred overnight. The ethanol was
evaporated under vacuo and HCl 0.5% was added to the residue to
pH=3. Extracted with Ethyl Acetate and concentrated to give the
title product as a mixture of two oximes. MS(ES) for
C.sub.26H.sub.2NO: [M+H].sup.+: 430.2, [M-H].sup.-: 428.2.
EXAMPLE 20
[0688]
(2S)-3-[4-(3-{4-[(4-Fluoro-phenyl)-hydroxyimino-methyl]-phenoxy}-pr-
op-1-ynyl)-phenyl]-2-methoxy-propionic acid 60
[0689]
(2S)-3-(4-{3-[4-(4-Fluoro-benzoyl)-phenoxy]-prop-1-ynyl}-phenyl)-2--
methoxy-propionic acid from Example 12 (0.01 mmol, 1 eq) was mixed
with Hydroxylamine chlorydrate (4 eq), pyridine (10 eq) and Ethanol
(2 ml) and the mixture reaction was stirred overnight. The ethanol
was evaporated under vacuo and HCl 0.5% was added to the residue to
pH=3. Extracted with Ethyl Acetate and concentrated to give the
title product as a mixture of two oximes. MS(ES) for
C.sub.26H.sub.22FNO.sub.5 [M+H].sup.+: 448.2, [M-H].sup.-:
446.2.
EXAMPLE 21
[0690]
(2S)-3-{4-[5-(Biphenyl-4-yloxy)-pent-1-ynyl]-phenyl}-2-methoxy-prop-
ionic acid: 61
[0691] Step A
[0692]
(2S)-3-[4-(5-Hydroxy-pent-1-ynyl)-phenyl]-2-methoxy-propionic acid
ethyl ester 62
[0693] This compound was prepared form 4-pentyn-1-ol following the
procedure described in Example 1, Step B. Yellow-brown oil.
.sup.1H-NMR (200.15 MHz, CDCl.sub.3): .delta. 7.33 (d, 2H, J=8.1),
7.16 (d, 2H, J=8.1), 4.17 (q, 2H, J=7.3), 3.92 (dd, 1H, J=7.3,
5.7), 3.80 (t, 2H, J=6.5), 3.34 (s, 3H), 3.01 (s, 1H), 2.98 (d, 1H,
J=2.4), 2.68 (t, 2H, J=6.2), 1.86 (br, 1H), 1.23 (t, 3H,
J=7.3).
[0694] Step B
[0695]
(2S)-3-{4-[5-(Biphenyl-4-yloxy)-pent-1-ynyl]-phenyl}-2-methoxy-prop-
ionic acid
[0696] The title compound was prepared from
(2S)-3-[4-(5-hydroxy-pent-1-yn- yl)-phenyl]-2-methoxy-propionic
acid ethyl ester and 4-phenylphenol via the standard Mitsunobu
coupling-hydrolysis procedure (Standard Procedure A) to produce a
white oily solid. .sup.1H-NMR (200.15 MHz, CDCl.sub.3): .delta.
7.56-7.28 (m, 9H), 7.15 (d, 2H, J=8.4), 6.98 (d, 2H, J=8.8), 4.15
(t, 2H, J=6.2), 3.97 (dd, 1H, J=7.7, 4.4), 3.36 (s, 3H), 3.11 (dd,
1H, J=14.3, 4.4), 2.97 (dd, 1H, J=14.3, 7.7), 2.62 (t, 2H, J=7.0),
2.08 (qn, 2H, J=6.6).
EXAMPLE 22
[0697]
(2S)-2-Methoxy-3-{4-[5-(4-phenoxy-phenoxy)-pent-1-ynyl]-phenyl}-pro-
pionic acid: 63
[0698] The title compound was prepared from
(2S)-3-[4-(5-hydroxy-pent-1-yn- yl)-phenyl]-2-methoxy-propionic
acid (Example 21, Step A) and 4-phenoxyphenol via the standard
Mitsunobu coupling-hydrolysis procedure (Standard Procedure A) to
produce a white oily solid. .sup.1H-NMR (200.15 MHz, CDCl.sub.3):
.delta. 7.26-7.19 (m, 4H), 7.07 (d, 2H, J=8.3), 6.98-6.78 (m, 7H),
4.01 (t, 2H, J=5.9), 3.91 (dd, 1H, J=7.3, 4.3), 3.30 (s, 3H), 3.05
(dd, 1H, J=14.2, 4.3), 2.90 (dd, 1H, J=14.2, 7.5), 2.54 (t, 2H,
J=6.7), 1.98 (qn, 2H, J=6.4). MS (ES) for
C.sub.27H.sub.26O.sub.5[M+N- H.sub.4].sup.+: 448, [M+Na].sup.+:
453.
EXAMPLE 23
[0699]
(2S)-3-{4-[5-(4-Benzoyl-phenoxy)-pent-1-ynyl]-phenyl}-2-methoxy-pro-
pionic acid 64
[0700] The title compound was prepared from
(2S)-3-[4-(5-hydroxy-pent-1-yn- yl)-phenyl]-2-methoxy-propionic
acid (Example 21, Step A) and 4-hydroxybenzophenone via the
standard Mitsunobu coupling-hydrolysis procedure (Standard
Procedure A) to produce a white oily solid. .sup.1H-NMR (200.15
MHz, CDCl.sub.3): .delta. 7.82-7.70 (m, 3H), 7.54-7.43 (m, 4H),
7.31-7.23 (m, 2H), 7.14 (d, 2H, J=8.1), 6.95 (d, 2H, J=8.8), 4.19
(d, 2H, J=5.9), 3.96 (dd, 1H, J=7.7, 4.4), 3.34 (s, 3H), 3.09 (dd,
1H, J=14.3, 4.4), 2.95 (dd, 1H, J=14.3, 7.7), 2.61 (t, 2H, J=7.0),
2.08 (qn, 2H, J=0.6).
EXAMPLE 24
[0701]
(2S)-3-{4-[5-(4-Benzyl-phenoxy)-pent-1-ynyl]-phenyl}-2-methoxy-prop-
ionic acid 65
[0702] Step A
[0703] 3-[4-(5-Bromo-pent-1-ynyl)-phenyl]-2-methoxy-propionic acid
ethyl ester 66
[0704] To a solution of
(2S)-3-[4-(5-Hydroxy-pent-1-ynyl)-phenyl]-2-methox- y-propionic
acid ethyl ester from Example 21, Step A (0.17 mmol, 1 eq) in
dichloromethane (5 ml) and CBr.sub.4 (0.34 mmol, 2 eq) at 0.degree.
C., Ph.sub.3P was added (0.34 mmol, 2 eq) partionwise and the
mixture reaction was stirred 1 hour the solvent was removed under
vacuo and the residue purified by flash chromatography using
Hexane/Ethyl acetate as eluent (6:1) to give the title product in
85% yield.
[0705] Step B
[0706]
(2S)-3-{4-[5-(4-Benzyl-phenoxy)-pent-1-ynyl]-phenyl}-2-methoxy-prop-
ionic acid
[0707] A solution of
3-[4-(5-Bromo-pent-1-ynyl)-phenyl]-2-methoxy-propioni- c acid ethyl
ester from Step A (0.1 mmol, 1 eq) in 0.7 ml of DMF in a
16.times.100 mm tube treated with 4-hydroxydiphenylmethane (0.11
mmol, 1.1 eq) and Cesium Carbonate (0.3 mmol, 3 eq) and stirred at
room temperature overnight. The reactants were filtered and washed
with DMF several times. The solvent was evaporated under vacuo and
the residue reconstituted in a mixture of Ethanol (2 ml) and NaOH
(1M) (1 ml) and stirred at room temperature until reaction is
completed by HPLC-MS. Then HCl (1M) was added (until pH=3) and the
solvent were eliminated under vacuo. The residue was reconstituted
in CH.sub.2Cl.sub.2/H.sub.2O and filtered through a hidrofobic
syringer. The organic layer was separated, concentrated and
purified by HPLC-MS to get the title compound. MS(ES) for
C.sub.28H.sub.28O.sub.4[M+NH.sub.4].sup.+: 446.2.
EXAMPLE 25
[0708]
(2S)-3-(4-{5-[4-(4-Fluoro-benzoyl)-phenoxy]-pent-1-ynyl}-phenyl)-2--
methoxy-propionic acid 67
[0709] The title compound was prepared from
3-[4-(5-Bromo-pent-1-ynyl)-phe- nyl]-2-methoxy-propionic acid ethyl
ester from Example 24, Step A and 4-fluoro-4-hydroxybenzophenone in
a manner analogous to that described for Example 24, Step B. MS(ES)
for C.sub.28H.sub.25F.sub.3O.sub.5[M+H].su- p.+: 461.2.
EXAMPLE 26
[0710]
(2S)-2-Methoxy-3-(4-{5-[4-(4-trifluoromethyl-phenoxy)-phenoxy-pent--
1-ynyl}-phenyl)-propionic acid 68
[0711] The title compound was prepared from
3-[4-(5-Bromo-pent-1-ynyl)-phe- nyl]-2-methoxy-propionic acid ethyl
ester
[0712] From Example 24, Step A and
4-(4-trifluoromethylphenoxy)phenol in a manner analogous to that
described for Example 24, Step B. MS(ES) for
C.sub.28H.sub.25F.sub.3O.sub.5[M+NH.sub.4].sup.+: 516.2.
EXAMPLE 27
[0713]
(2S)-2-Methoxy-3-{4-[5-(4-oxo-2-phenyl-4H-chromen-7-yloxy)-pent-1-y-
nyl]-phenyl}-propionic acid 69
[0714] The title compound was prepared from
3-[4-(5-Bromo-pent-1-ynyl)-phe- nyl]-2-methoxy-propionic acid ethyl
ester from Example 24, Step A and 7-hydroxyflavone in a manner
analogous to that described for Example 24, Step B. MS(ES) for
C.sub.30H.sub.26O.sub.6[M+H].sup.+:483.2.
EXAMPLE 28
[0715]
(2S)-2-Methoxy-3-{4-[5-(4-oxo-2-phenyl-4H-chromen-6-yloxy)-pent-1-y-
nyl]-phenyl}-propionic acid 70
[0716] The title compound was prepared from
3-[4-(5-Bromo-pent-1-ynyl)-phe- nyl]-2-methoxy-propionic acid ethyl
ester from Example 24, Step A and 6-hydroxyflavone in a manner
analogous to that described for Example 24, Step B. MS(ES) for
C.sub.30H.sub.26O.sub.6[M+H].sup.+:483.2
EXAMPLE 29
[0717]
(2S)-2-Methoxy-3-(4-{5-[4-(1-methyl-1-phenyl-ethyl)-phenoxy]-pent-1-
-ynyl}-phenyl)-propionic acid 71
[0718] The title compound was prepared from
3-[4-(5-Bromo-pent-1-ynyl)-phe- nyl]-2-methoxy-propionic acid ethyl
ester from Example 24, Step A and 4-cumylphenol in a manner
analogous to that described for Example 24, Step B. MS(ES) for
C.sub.30H.sub.32O.sub.4 [M+NH.sub.4].sup.+: 474.3
EXAMPLE 30
[0719]
(2S)-2-Methoxy-3-{4-[5-(9-oxo-9H-fluoren-2-yloxy-pent-1-ynyl]-pheny-
l}-propionic acid 72
[0720] The title compound was prepared from
3-[4-(5-Bromo-pent-1-ynyl)-phe- nyl]-2-methoxy-propionic acid ethyl
ester from Example 24, Step A and 2-hydroxy-9-fluorenone in a
manner analogous to that described for Example 24, Step B. MS(ES)
for C.sub.8H.sub.24O.sub.5[M+H].sup.+:441.2.
EXAMPLE 31
[0721]
(2S)-2-Methoxy-3-{4-[5-(3-phenylamino-phenoxy)-pent-1-ynyl]-phenyl}-
-propionic acid 73
[0722] The title compound was prepared from
3-[4-(5-Bromo-pent-1-ynyl)-phe- nyl]-2-methoxy-propionic acid ethyl
ester from Example 24 Step A and 3-hydroxydiphenylamine in a manner
analogous to that described for Example 24, Step B. MS(ES) for
C.sub.27H.sub.27NO.sub.4[M+H].sup.+:430.2.
EXAMPLE 32
[0723]
(2S)-3-(4-{5-[4-(2-Fluoro-benzoyl)-phenoxy]-pent-1-ynyl}-phenyl)-2--
methoxy-propionic acid 74
[0724] The title compound was prepared from
3-[4-(5-Bromo-pent-1-ynyl)-phe- nyl]-2-methoxy-propionic acid ethyl
ester from Example 24, Step A and 2-fluoro-4'-hydroxybenzophenone
in a manner analogous to that described for Example 24, Step B.
MS(ES) for C.sub.28H.sub.25FO.sub.5[M+H].sup.+:46- 1.2.
EXAMPLE 33
[0725]
(2S)-2-Methoxy-3-{4-[5-(3-phenyl-benzofuran-6-yloxy)-pent-1-ynyl]-p-
henyl}-propionic acid 75
[0726] The title compound was prepared from
3-[4-(5-Bromo-pent-1-ynyl)-phe- nyl]-2-methoxy-propionic acid ethyl
ester from Exapmle 24, Step A and 6-hydroxy-4-phenylbenzophenone in
a manner analogous to that described for Example 24, Step B. MS(ES)
for C.sub.29H.sub.26O.sub.5[M+H].sup.+:455- .2.
EXAMPLE 34
[0727]
(2S)-3-(4-{5-[3-(4-Fluoro-phenyl)-benzofuran-6-yloxy]-pent-1-ynyl}--
phenyl)-2-methoxy-propionic acid 76
[0728] The title compound was prepared from
3-[4-(5-Bromo-pent-1-ynyl)-phe- nyl]-2-methoxy-propionic acid ethyl
ester from Example 24, Step A and
3-(4'-fluorophenyl)-6-hydroxybenzophenone in a manner analogous to
that described for Example 24, Step B. MS(ES) for
C.sub.29H.sub.25PO.sub.5[M+H- ].sup.+:473.2.
EXAMPLE 35
[0729]
(2S)-2-Methoxy-3-{4-[5-(4-phenylacetyl-phenoxy)-pent-1-ynyl]-phenyl-
}-propionic acid 77
[0730] The title compound was prepared from
3-[4-(5-Bromo-pent-1-ynyl)-phe- nyl]-2-methoxy-propionic acid ethyl
ester from Example 24, Step A and benzyl-4-hydroxyphenylketone in a
manner analogous to that described for Example 24, Step B. MS(ES)
for C.sub.29H.sub.25O.sub.5[M-H].sup.-:455.2.
EXAMPLE 36
[0731]
(2S)-3-{4-[5-Butyl-phenoxy)-pent-1-ynyl]-phenyl}-2-methoxy-propioni-
c acid 78
[0732] The title compound was prepared from
3-[4-(5-Bromo-pent-1-ynyl)-phe- nyl]-2-methoxy-propionic acid ethyl
ester from Example 24, Step A and 4-N-butylphenol in a manner
analogous to that described for Example 24, Step B. MS(ES) for
C.sub.25H.sub.30O.sub.4[M-H].sup.-:393.2.
EXAMPLE 37
[0733]
(2S)-3-[4-(5-{4-[(2-Fluoro-phenyl)-hydroxyimino-methyl]-phenoxy}-pe-
nt-1-ynyl)-phenyl]-2-methoxy-propionic 79
[0734]
(2S)-3-(4-{5-[4-(2-Fluoro-benzoyl)-phenoxy]-pent-1-ynyl}-phenyl)-2--
methoxy-propionic acid from Example 32, (1 eq) was mixed with
Hydroxylamine chlorydrate (4 eq), pyrydine (10 eq) and Ethanol (2
ml) and the mixture reaction was stirred overnight. The ethanol was
evaporated under vacuo and HCl 6.5% was added to the residue to
pH=3. Extracted with Ethyl Acetate and concentrated to give the
title product as a mixture of two oximes. MS(ES) for
C.sub.28H.sub.26FNO.sub.5 [M+H].sup.+: 476.2, [M-H].sup.-:
474.2.
EXAMPLE 38
[0735]
(2S)-3-[4-(5-{4-[(4-Fluoro-phenyl)-hydroxyimino-methyl]-phenoxy}-pe-
nt-1-ynyl)-phenyl]-2-methoxy-propionic acid 80
[0736]
(2S)-3-(4-{5-[4-(4-Fluoro-benzoyl)-phenoxy]-pent-1-ynyl}-phenyl)-2--
methoxy-propionic acid from Example 25 (1 eq) was mixed with
Hydroxylamine chlorydrate (4 eq), pyrydine (10 eq) and Ethanol (2
ml) and the mixture reaction was stirred overnight. The ethanol was
evaporated under vacuo and HCl 0.5% was added to the residue to
pH=3. Extracted with Ethyl Acetate and concentrated to give the
title product as a mixture of two oximes. MS(ES) for
C.sub.28H.sub.26FNO.sub.5 [M+H].sup.+: 476.2, [M-H].sup.-:
474.2.
EXAMPLE 39
[0737]
(2S)-3-(4-{5-[4-Hydroxyimino-phenyl-methyl)-phenoxy]-pent-1-ynyl}-p-
henyl)-2-methoxy-propionic acid 81
[0738]
(2S)-3-{4-[5-(4-Benzoyl-phenoxy)-pent-1-ynyl]-phenyl}-2-methoxy-pro-
pionic acid from Example 23, (1 eq) was mixed with Hydroxylamine
chlorydrate (4 eq), pyrydine (10 eq) and Ethanol (2 ml) and the
mixture reaction was stirred overnight. The ethanol was evaporated
under vacuo and HCl 0.5% was added to the residue to pH=3.
Extracted with Ethyl Acetate and concentrated to give the title
product as a mixture of two oximes: MS(ES) for
C.sub.28H.sub.27NO.sub.5 [M+H].sup.+: 458.2.
EXAMPLE 40
[0739]
(2S)-3-{4-[4-(Biphenyl-4-yloxy)-but-1-ynyl]-phenyl}-2-methoxy-propi-
onic acid: 82
[0740] Step A
[0741] Toluene-4-sulfonic acid but-3-ynyl ester 83
[0742] A solution of 3-butyn-1-ol (1 mL, 13.31 mmol),
p-toluenesulphenyl chloride (2.519 g, 13.21 mmol), triethylamine
(2.03 mL, 14.53 mmol) and 4-dimethylaminopyridine (0.081 g, 0.66
mmol) in 20 mL of dichloromethane were stirred at room temperature
overnight. The solution was diluted with dichloromethane (20 mL),
washed with 0.5N HCl (40 mL) and brine (40 mL), dried (MgSO.sub.4),
and concentrated to produce an oil (2.82 g, 95%). .sup.1H-NMR
(200.15 MHz, CDCl.sub.3): .delta. 7.80 (d, 2H, J=8.3), 7.35 (d, 2H,
J=8.1), 4.10 (t, 2H, J=7.0), 2.55 (dt, 2H, J=2.7, 7.0), 2.45 (s,
3H), 1.97 (t, 1H, J=2.7).
[0743] Step B
[0744] 4-But-3-ynyloxy-biphenyl 84
[0745] A solution of 4-phenylphenol (0.774 g, 4.55 mmol) and
potassium tert-butoxide (0.51 g, 4.55 mmol) in toluene (20 mL) was
stirred for 1 h at room temperature. Sodium iodide (0.068 g, 0.45
mmol) and toluene-4-sulfonic acid but-3-ynyl ester (1.02 g, 4.55
mmol) were added, and the mixture heated to reflux for 24 hours.
The mixture was cooled to room temperature, diluted with diethyl
ether (20 mL), washed with water (2.times.20 mL). The organic layer
was dried (MgSO.sub.4) and concentrated under vacuum. The residue
was purified by silica gel chromatography (silica gel,
hexanes/ethyl acetate 3:1, R.sub.f0.57) to give an oil (140 mg,
14%). .sup.1H-NMR (200.15 MHz, CDCl.sub.3): .delta. 7.57-7.50 (m,
4H), 7.46-7.38 (m, 2H), 7.32 (d, 1H, J=7.3), 7.02-6.95 (m, 2H),
4.15 (t, 2H, J=7.0), 2.71 (dt, 2H, J=2.7, 7.3), 2.06 (t, 1H,
J=2.7).
[0746] Step C
[0747]
(2S)-3-{4-[4-(Biphenyl-4-yloxy)-but-1-ynyl]-phenyl}-2-methoxy-propi-
onic acid ethyl ester 85
[0748] To a solution of
(2S)-2-methoxy-3-(4-trifluoro-methanesulfonyloxy-p-
henyl)-propionic acid ethyl ester (1.157 g, 3.4 mmol) (Example 1,
Step A) in 30 mL of degassed piperidine was added
4-but-3-ynyloxy-biphenyl (0.9 g, 4.85 mmol),
tetrakis(triphenylphosphine)palladium (0) (0.196 g, 0.17 mmol),
triphenylphosphine (0.09 g, 0.34 mmol), and cooper (I) iodide
(0.065 g, 0.34 mmol). The solution was stirred for 3 h at
80.degree. C. and cooled to room temperature. The solvent was
evaporated under vacuum, and the residue was purified by column
chromatography (silica gel, hexanes/diethyl ether 9:1, R.sub.f0.27)
to a brown oil (0.7 g, 48%). .sup.1H-NMR (200.15 MHz, CDCl.sub.3):
.delta. 7.58-7.30 (m, 9H), 7.17 (d, 2H, J=8.0), 7.02 (d, 2H,
J=8.9), 4.22 (t, 2H, J=7.3), 4.18 (q, 2H, J=7.0), 3.93 (dd, 1H,
J=7.3, 5.6), 3.35 (s, 3H), 3.02 (s, 1H), 2.99 (d, 1H, J=2.4), 2.92
(t, 2H, J=7.3), 1.24 (t, 3H, J=7.3).
[0749] Step D
[0750]
(2S)-3-{4-[4-(Biphenyl-4-yloxy)-but-1-ynyl]-phenyl}-2-methoxy-propi-
onic acid
[0751] The title compound was prepared from
(2S)-3-{4-[4-(biphenyl-4-yloxy-
)-but-1-ynyl]-phenyl}-2-methoxy-propionic acid ethyl ester via the
standard hydrolysis procedure C. The residue was purified by
chromatography (silica gel hexanes/ethyl acetate/acetic acid
50:50:1, R.sub.f0.25) to produce a white solid (86%). .sup.1H-NMR
(200.15 MHz, CDCl.sub.3): .delta. 7.57-7.51 (m, 4H), 7.45-7.30 (m,
5H), 7.19 (d, 2H, J=8.0), 7.01 (d, 2H, J=8.8), 4.20 (t, 2H, J=6.9),
3.98 (dd, 1H, J=7.7, 4.4), 3.37 (s, 3H), 3.11 (dd, 1H, J=14.3,
4.4), 3.00 (dd, 1H, J=14.3, 7.7), 2.91 (t, 2H, J=7.0).
EXAMPLE 41
[0752]
(2S)-2-Methoxy-3-{4-[4-(4-phenoxy-phenoxy)-but-1-ynyl]-phenyl}-prop-
ionic acid 86
[0753] Step A
[0754] 1-But-3-ynyloxy-4-phenyloxybenzene 87
[0755] This compound was prepared from 4-phenoxyphenol and
toluene-4-sulfonic acid but-3-ynyl ester (Example 40, Step A)
following the procedure described in Example 40, Step B.
.sup.1H-NMR (200.15 MHz, CDCl.sub.3): .delta. 77.35-7.26 (m, 2H),
7.05-6.87 (m, 5H), 4.09 (t, 2H, J=7.0), 2.69 (dt, 2H, J=2.4, 7.0),
2.05 (t, 1H, J=2.1).
[0756] Step B
[0757]
(2S)-2-Methoxy-3-{4-[4-(4-phenoxy-phenoxy)-but-4-ynyl]-phenyl}-prop-
ionic acid
[0758] The title compound was prepared from
1-but-3-ynyloxy-4-phenyloxyben- zene and
(2S)-2-methoxy-3-(4-trifluoromethanesulfonyloxy-phenyl)-propionic
acid ethyl ester (Example 1, Step A) following the procedure
described in Example 40, Step C. The ethyl ester derivative was
contaminated with starting triflate. The mixture was hydrolyzed
using the Standard Procedure C. The residue was purified by
chromatography (silica gel, hexanes/ethyl acetate-Acetic acid
50:50:1, R.sub.f0.25) to produce a white solid (7%): .sup.1H-NMR
(200.15 MHz, CDCl.sub.3): .delta. 7.35-7.28 (m, 4H), 7.16 (d, 2H,
J=8.0), 7.02-6.87 (1H, 7H), 4.13 (t, 2H, J=7.0), 3.97 (dd, 1H,
J=7.7, 4.4), 3.36 (s, 3H), 3.11 (dd, 1H, J=14.3, 4.4), 2.97 (dd,
1H, J=14.3, 7.7), 2.87 (t, 2H, J=7.0). MS (ES) fro
C.sub.26H.sub.24O.sub.5 [M+NH.sub.4].sup.+: 434.2, [M+Na].sup.+:
439.2.
EXAMPLE 42
[0759]
(2S)-3-{4-[4-(4-Benzoyl-phenoxy)-but-1-ynyl]-phenyl}-2-methoxy-prop-
ionic acid 88
[0760] Step A
[0761] (4-But-3-ynyloxy-phenyl)-phenyl-methanone 89
[0762] This compound was prepared from 4-hydroxybenzophenone and
toluene-4-sulfonic acid but-3-ynyl ester (Example 40, Step A)
following the procedure described in Example 40, Step B (8%).
.sup.1H-NMR (200.15 MHz, CDCl.sub.3): .delta. 7.84-7.73 (m, 4H),
7.57-7.43 (m, 3H), 6.97 (d, 2H, J=8.6), 4.18 (t, 2H, J=7.0), 2.73
(dt, 2H, J=2.7, 7.0), 2.06 (t, 1H, J=2.7).
[0763] Step B
[0764]
(2S)-3-{4-[4-(4-Benzoyl-phenoxy)-but-1-ynyl]-phenyl}-2-methoxy-prop-
ionic acid ethyl ester 90
[0765] This compound was prepared from
(4-but-3-ynyloxy-phenyl)-phenylmeth- anone and
(2S)-2-Methoxy-3-(4-trifluoromethane-sulfonyloxy-phenyl)-propion-
ic acid ethyl ester (Example 1, Step A) following the procedure
described in Example 38, Step C (66%). .sup.1H-NMR (200.15 MHz,
CDCl.sub.3): .delta. 37.85-7.73 (m, 4H), 7.57-7.43 (m; 3H), 7.34
(d, 2H, J=8.1), 7.16 (d, 2H, J=8.3), 7.00 (d, 2H, J=8.6), 4.25 (t,
2H, J=7.0), 4.18 (q, 2H, J=7.0), 3.92 (dd, 1H, J=7.3, 5.6), 3.34
(s, 3H), 3.01 (s, 1H), 2.98 (d, 1H, J=3.5), 2.93 (t, 2H, J=7.0),
1.23 (t, 3H, J=7.3).
[0766] Step C
[0767]
(2S)-3-{4-[4-(4-Benzoyl-phenoxy)-but-1-ynyl]-phenyl}-2-methoxy-prop-
ionic acid
[0768] The title compound was prepared from
(2S)-3-{4-[4-(4-benzoyl-phenox-
y)-but-1-ynyl]-phenyl}-2-methoxy-propionic acid ethyl ester via the
standard hydrolysis procedure C to produce a white solid.
.sup.1H-NMR (200.15 MHz, CDCl.sub.3): .delta. 7.83-7.71 (m, 4H),
7.55-7.44 (m, 3H), 7.32 (d, 2H, J=8.0), 7.16 (d, 2H, J=8.4), 6.97
(d, 2H, J=9.1), 4.22 (t, 2H, J=7.0), 3.96 (dd, 1H, J=7.7, 4.4),
3.35 (s, 3H), 3.10 (dd, 1H, J=13.9, 4.4), 2.98 (dd, 1H, J=13.9,
7.7), 2.91 (t, 2H, J=7.0).
EXAMPLE 43
[0769]
(2S)-3-(4-{4-[4-(Hydroxyimino-phenyl-methyl)-phenoxy]-but-1-ynyl}-p-
henyl)-2-methoxy-propionic acid 91
[0770]
(2S)-3-{4-[4-(4-Benzoyl-phenoxy)-but-1-ynyl]-phenyl}-2-methoxy-prop-
ionic acid from Example 42, (1 eq) was mixed with Hydroxylamine
chlorydrate (4 eq), pyrydine (10 eq) and Ethanol (2 ml) and the
mixture reaction was stirred overnight. The ethanol was evaporated
under vacuo and HCl 0.5% was added to the residue to pH=3.
Extracted with Ethyl Acetate and concentrated to give the title
product as a mixture of two oximes. MS (ES) for
C.sub.27H.sub.25NO.sub.5 [M+H].sup.+: 444.2
EXAMPLE 44
[0771]
(2S)-3-(4-{4-[4-(4-Fluoro-benzoyl)-phenoxy]-but-1-ynyl}-phenyl)-2-m-
ethoxy-propionic acid 92
[0772] Step A
[0773] (4-But-3-ynyloxy-phenyl)-(4-fluoro-phenyl)-methanone 93
[0774] This compound was prepared from 4-fluoro-hydroxybenzophenone
and toluene-4-sulfonic acid but-3-ynyl ester (Example 40, Step A)
following the procedure described in Example 40, Step B.
[0775] Step B
[0776]
(2S)-3-(4-{4-[4-(4-Fluoro-benzyl)-phenoxy]-but-1-phenyl)-2-methoxy--
propionic acid
[0777] The title compound was prepared from
(4-But-3-ynyloxy-phenyl)-(4-fl- uoro-phenyl)-methanone and
(2S)-2-methoxy 3-(4-trifluoromethanesulfonyloxy- -phenyl)-propionic
acid ethyl ester (Example 1, Step A) following the procedure
described in Example 40, Step C. The ethyl ester derivative was
contaminated with starting triflate. The mixture was hydrolyzed
using the standard hydrolysis procedure C. The residue was purified
by chromatography. MS(ES) for C.sub.27H.sub.23FO [M+H].sup.+:
447.2.
EXAMPLE 45
[0778]
(2S)-3-(4-{4-[3-(4-Fluoro-phenyl)-benzofuran-6-yloxy]-but-1-ynyl}-p-
henyl)-2-methoxy-propionic acid 94
[0779] Step A
[0780] 6-But-3-ylnyloxy-3-(4-fluoro-phenyl)-benzofuran 95
[0781] This compound was prepared from
6-hydroxy-3-(4-fluorophenyl)benzofu- rane and toluene-4-sulfonic
acid but-3-ynyl ester (Example 40, Step A) following the procedure
described in Example 40, Step 13.
[0782] Step B
[0783]
(2S)-3-(4-{4-[3-(4-Fluoro-phenyl)-benzofuran-6-yloxy]-but-1-ynyl}-p-
henyl)-2-methoxy-propionic acid
[0784] The title compound was prepared from
6-But-3-ynyloxy-3-(4-fluoro-ph- enyl)-benzofuran and
(2S)-2-methoxy-3-(4-trifluoromethanesulfonyloxy-pheny- l)-propionic
acid ethyl ester Example 1, Step A) following the procedure
described in Example 40, Step C. The ethyl ester derivative was
contaminated with starting triflate. The mixture was hydrolyzed
using the Standard Procedure C. The residue was purified by
chromatography. MS(ES) for C.sub.28H.sub.23FO.sub.5 [M-H].sup.-:
457.2
EXAMPLE 46
[0785]
(2S)-2-Methoxy-3-(4-{4-[4-(4-trifluoromethyl-phenoxy)-phenoxy]-but--
1-ynyl}-phenyl)-propionic acid 96
[0786] Step A
[0787] 4-(3-butynyloxy)-4'-trifluoromethylphenyloxy phenyl 97
[0788] This compound was prepared from trifluoromethylphenoxyphenol
and toluene sulfonic acid but-3-ynyl ester Example 40, Step A)
following the procedure described in Example 40, Step B.
[0789] Step B
[0790]
(2S)-2-Methoxy-3-(4-{4-[4-(4-trifluoromethyl-phenoxy)-phenoxy]-but--
1-ynyl}-phenyl)-propionic acid
[0791] The title compound was prepared from
4-(3-butynyloxy)-4'-trifluorom- ethylphenyloxy phenyl and
(2S)-2-methoxy-3-(4-trifluoromethanesulfonyloxy-- phenyl)-propionic
acid ethyl ester (Example 1, Step A) following the procedure
described in Example 40, Step C. The ethyl ester derivative was
contaminated with starting triflate. The mixture was hydrolyzed
using the Standard Procedure C. The residue was purified by
chromatography. MS(ES) for C.sub.27H.sub.23F.sub.3O.sub.5
[M-H].sup.-: 483.2
EXAMPLE 47
[0792]
(2S)-2-Methoxy-3-{4-[4-(4-oxo-2-phenyl-4H-chromen-7-yloxy-but-1-yny-
l]-phenyl}-propionic acid 98
[0793] Step A
[0794] 3-[4-(4-Hydroxy-but-1-ynyl)-phenyl]-2-methoxy-propionic acid
ethyl ester 99
[0795] This compound was prepared form 4-butyn-1-ol following the
procedure described in Example 1, Step B.
[0796] Step B
[0797]
(2S)-2-Methoxy-3-{4-[4-(4-oxo-2-phenyl-4H-chromen-7-yloxy)-but-1-yn-
yl]-phenyl}-propionic acid
[0798] The title compound was prepared from 7-hydroxyflavone by the
Standard coupling-hydrolisis Procedure A but using for the
Mitsounobu reaction toluene as solvent and DIAD instead DEAD.
MS(ES) for C.sub.29H.sub.24O.sub.6 [M+H].sup.+: 429.2.
EXAMPLE 48
[0799]
(2S)-2-Methoxy-3-{4-[4-(4-oxo-2-phenyl-4H-chromen-6-yloxy)-but-1-yn-
yl]-phenyl}-propionic acid 100
[0800] The title compound was prepared from
3-[4-(4-Hydroxy-but-1-ynyl)-ph- enyl]-2-methoxy-propionic acid
ethyl ester from Example 47, Step A and 6-hydroxyflavone following
the standard coupling-hydrolysis procedure A using toluene as
solvent and DIAD instead DEAD. MS(ES) for C.sub.29H.sub.24O.sub.6
[M+H].sup.+: 469.2.
EXAMPLE 49
[0801]
(2S)-2-Methoxy-3-{4-[6-(4-phenoxy-phenoxy)-hex-1-ynyl]-phenyl}-prop-
ionic acid 101
[0802] Step A
[0803] (2S)-3-[4-(6-Hydroxy-hex-1-ynyl)-phenyl]-2-methoxy-propionic
acid ethyl ester 102
[0804] To a solution of (2S)-(3-(4-iodophenyl)-2-methoxy-propionic
acid ethyl ester (1.6 g, 4.81 mmol) in 100 mL of degassed
piperidine was added 5-hexin-1-ol (0.709 g, 724 mmol),
tetrakis(triphenylphosphine)palladium (0) (0.278 g, 0.24 mmol),
triphenylphosphine (0.125 g, 0.48 mmol), and cooper (I) iodide
(0.091 g, 0.48 mmol). The solution was stirred for 3 hours at
80.degree. C. and cooled to room temperature. The solvent was
evaporated under vacuum, and the residue was purified by column
chromatography (silica gel, hexanes/ethyl acetate 3:1 to give title
compound as a yellow oil (1.18 g, 74% yield). MS(ES) for
C.sub.18H.sub.24O.sub.4[M+NH.sub.4].sup.+: 322.2.
[0805] Step B
[0806]
(2S)-2-Methoxy-3-{4-[6-(4-phenoxy-phenoxy)-hex-1-ynyl]-phenyl}-prop-
ionic acid
[0807] The title compound was prepared from
3-[4-(6-Hydroxy-hex-1-ynyl)-ph- enyl]-2-methoxy-propionic acid
ethyl ester and 4-phenoxyphenol via the standard Mitsunobu
coupling-hydrolysis procedure (Standard Procedure A) to produce the
title compound. MS(ES) for C.sub.28H.sub.28O.sub.5[M+H].su- p.+:
445.2
EXAMPLE 50
[0808]
(2S)-3-{4-[6-(4-Benzoyl-phenoxy)-hex-1-ynyl]-phenyl}-2-methoxy-prop-
ionic acid 103
[0809] The title compound was prepared from
3-[4-(6-Hydroxy-hex-1-ynyl)-ph- enyl]-2-methoxy-propionic acid
ethyl ester (Example 49, Step A) and 4-hydroxybenzophenone via the
standard Mitsunobu coupling-hydrolysis procedure (Standard
Procedure A) to produce the title compound. MS(ES) for
C.sub.29H.sub.28O.sub.5 [M+H].sup.+: 457.2
EXAMPLE 51
[0810]
(2S)-3-{4-[6-(Biphenyl-4-yloxy)-hex-1-ynyl]-phenyl}-2-methoxy-propi-
onic acid 104
[0811] The title compound was prepared from
3-[4-(6-Hydroxy-hex-1-ynyl)-ph- enyl]-2-methoxy-propionic acid
ethyl ester (Example 49, Step A) and 4-phenylphenol via the
standard Mitsunobu coupling-hydrolysis procedure (Standard
Procedure A) to produce the title compound. MS(ES) for
C.sub.28H.sub.28O.sub.4[M+NH.sub.4].sup.+: 446.2.
EXAMPLE 52
[0812]
(2S)-3-{4-[5-(Biphenyl-4-yloxy)-pentanoyl]-phenyl}-2-methoxy-propio-
nic acid 105
[0813] A solution of triphenylphosphine (0.24 g, 0.915 mmol) in 5
mL of dry THF was treated at 0.degree. C. with
diethylazodicarboxylate (0.159 g, 0.915 mmol) and stirred for 20
min. A solution of
(2S)-3-[4-(5-hydroxy-pent-1-ynyl)-phenyl]-2-methoxy-propionic acid
ethyl ester (Example 21, Step A) (0.18 g, 0.61 mmol) and
4-phenylphenol (0.156 g, 0.915 mmol) in 2 mL of dry BF was added,
and the mixture was stirred at room temperature overnight. The
mixture was concentrated under vacuum and purified by silica gel
chromatography (silica gel, hexanes/ethyl acetate 10:1 to 3:1).
Fractions with R.sub.fs 0.48 and 0.45 (hexanes/ethyl acetate 2:1)
corresponding to the coupled compound and starting phenol,
respectively, were combined and concentrated. The mixture was
dissolved in 5 mL of methanol and was treated with a mixture of 75
mg of mercury (II) oxide and 4% sulfuric acid in water. The
solution was stirred at 55.degree. C. for 3 h, cooled to room
temperature, diluted with saturated aqueous NaHCO.sub.3 (20 mL),
and extracted with dichloromethane (4.times.20 mL). The combined
organic layers were washed with brine (20 mL), dried (MgSO.sub.4),
and concentrated. The residue was dissolved in 6 mL of methanol and
2 mL of 1N NaOH and stirred for 2 hours. The methanol was
evaporated under vacuum, and the aqueous solution was diluted with
brine (6 mL) and washed with diethyl ether (3.times.15 mL). The
aqueous layer was acidified with 1N HCl (pH 1-2) and extracted with
ethyl acetate (3.times.15 mL). The combined extracts were dried
(MgSO.sub.4) and concentrated to a white solid (19%). .sup.1H-NMR
(200.15 MHz, CDCl.sub.3): .delta. 7.89 (d, 2H, J=8.4), 7.55-7.23
(m, 9H), 6.93 (d, 2H, J=8.9), 4.06-3.99 (m, 3H), 3.38 (s, 3H), 3.18
(dd, 1H, J=4.3, 4.4), 3.03 (t+m, 3H, J=6.9), 1.96-1.86 (m, 4H).
EXAMPLE 53
[0814]
(2S)-3-{4-[5-(4-Benzoyl-phenoxy)-pentanoyl]-phenyl}-2-methoxy-propi-
onic acid 106
[0815] A solution of triphenylphosphine (0.915 mmol) in 5 mL of dry
THF was treated at 0.degree. C. with diethylazodicarboxylate (0.915
mmol) and stirred for 20 min. A solution of
(2S)-3-[4-(5-hydroxy-pent-1-ynyl)-pheny- l]-2-methoxy-propionic
acid ethyl ester (Example 21, Step A) (0.61 mmol) and
4-benzoylphenol (0.915 mmol) in 2 mL of dry THF was added, and the
mixture was stirred at room temperature overnight. The mixture was
concentrated under vacuum and purified by silica gel chromatography
(silica gel, hexanes/ethyl acetate 10:1 to 3:1). Fractions with
R.sub.fs 0.48 and 0.45 (hexanes/ethyl acetate 2:1) corresponding to
the coupled compound and starting phenol, respectively, were
combined and concentrated. The mixture was dissolved in 5 mL of
methanol and was treated with a mixture of 75 mg of mercury (II)
oxide and 4% sulfuric acid in water. The solution was stirred at
55.degree. C. for 3 hours, cooled to room temperature, diluted with
saturated aqueous NaHCO.sub.3 (20 mL), and extracted with
dichloromethane (4.times.20 mL). The combined organic layers were
washed with brine (20 mL), dried (MgSO.sub.4), and concentrated.
The residue was dissolved in 6 mL of methanol and 2 mL of 1N NaOH
and stirred for 2 hours. The methanol was evaporated under vacuum,
and the aqueous solution was diluted with brine (6 mL) and washed
with diethyl ether (3.times.15 mL). The aqueous layer was acidified
with 1N HCl (pH 1-2) and extracted with ethyl acetate (3.times.15
mL) then concentrated to give the title compound. .sup.1H-NMR
(CDCl.sub.3, 200.15 MHz): 7.91-7.72 (m, 5H), 7.56-7.32 (m, 6H),
6.92 (d, 2H, J=8.9), 4.12-4.03 (m, 3H), 3.42 (s, 3H), 3.19-3.05 (m,
4H), 1.95-1.92 (m, 4H).
EXAMPLE 54
[0816]
(2S)-2-Methoxy-3-{4-[5-(4-phenoxy-phenoxy)-pentanoyl]-phenyl}-propi-
onic acid 107
[0817] A solution of triphenylphosphine (0.915 mmol) in 5 mL of dry
THF was treated at 0.degree. C. with diethylazodicarboxylate (0.915
mmol) and stirred for 20 min. A solution of
(2S)-3-[4-(5-hydroxy-pent-1-ynyl)-pheny- l]-2-methoxy-propionic
acid ethyl ester (Example 21, Step A) (0.61 mmol) and
4-phenoxyphenol (0.915 mmol) in 2 mL of dry THF was added, and the
mixture was stirred at room temperature overnight. The mixture was
concentrated under vacuum and purified by silica gel chromatography
(silica gel, hexanes/ethyl acetate 10:1 to 3:1). Fractions with
R.sub.fs 0.48 and 0.45 (hexanes/ethyl acetate 2:1) corresponding to
the coupled compound and starting phenol, respectively, were
combined and concentrated. The mixture as dissolved in 5 mL of
methanol and was treated with a mire of 75 mg of mercury (II) oxide
and 4% sulfuric acid in water. The solution was stirred at
55.degree. C. for 3 hours, cooled to room temperature, diluted with
saturated aqueous NaHCO.sub.3 (20 mL), and extracted with
dichloromethane (4.times.20 mL). The combined organic layers were
washed with brine (20 mL), dried (MgSO.sub.4), and concentrated.
The residue was dissolved in 6 mL of methanol and 2 mL of 1N NaOH
and stirred for 2 hours. The methanol was evaporated under vacuum,
and the aqueous solution was diluted with brine (6 mL) and washed
with diethyl ether (3.times.15 mL). The aqueous layer was acidified
with 1N HCl (pH 1-2) and extracted with ethyl acetate (3.times.15
mL) then concentrated to give the title compound. .sup.1H-NMR
(CDCl3, 200.15 MHz): 7.91 (d, 2H, J=8.3), 7.36-7.27 (m, 4H),
7.07-6.83 (m, 7H), 4.08-3.96 (m, 3H), 3.41 (s, 3H), 3.22 (dd, 1H,
J=14.0, 4.3), 3.14-3.01 (m, 4H), 1.26 (s, 1H).
EXAMPLE 55
[0818]
3-{4-[4-(4-Benzoyl-phenoxy)-butyryl]-phenyl}-2-methoxy-propionic
acid 108
[0819] Step A
[0820]
(2S)-3-{4-[4-(4-Benzoyl-phenoxy)-butyryl]-phenyl}-2-methoxy-propion-
ic acid ethyl ester 109
[0821]
(2S)-3-{4-[4-(4-Benzoyl-phenoxy)-but-1-ynyl]-phenyl}-2-methoxy-prop-
ionic acid ethyl ester (Example 42, Step B) (0.08 g, 0.17 mmol) was
dissolved in 4 mL of methanol. To this solution was added 3 mL of a
solution of 0.075 g of mercury (II) oxide in 12 mL of 4% sulfuric
acid. The mixture was stirred at 55.degree. C. for 3 hours, cooled
to room temperature, and diluted with 20 mL saturated NaHCO.sub.3
solution. The mixture was extracted with of dichloromethane
(4.times.20 mL), and the combined organic layers were dried
(MgSO.sub.4), and concentrated. The residue was purified by silica
gel chromatography (silica gel, hexanes/ethyl acetate 3:1) to give
a yellow oil (72%). .sup.1H-NMR (200.15 MHz, CDCl.sub.3): .delta.
7.92 (d, 2H, J=8.6), 7.83-7.72 (m, 4H), 7.60-7.42 (m, 3H), 7.34 (d,
2H, J=8.6), 6.95 (d, 2H, J=8.9), 4.19 (q, 2H, J=7.3), 4.15 (t, 2H,
J=6.2), 3.97 (dd, 1H, J=7.3, 5.4), 3.35 (s, 3H), 3.19 (t, 2H,
J=7.0), 3.08 (d, 1H, J=5.1), 3.07 (d, 1H, J=7.5), 2.27 (qn, 2H,
J=6.2), 1.24 (t, 3H, J=7.3).
[0822] Step B
[0823]
3-{4-[4-(4-Benzoyl-phenoxy)-butyryl]-phenyl}-2-methoxy-propionic
acid
[0824] The title compound was prepared from
(2S)-3-{4-[4-(4-benzoyl-phenox-
y)-butyryl]-phenyl}-2-methoxy-propionic acid ethyl ester via the
standard hydrolysis procedure C. White solid (71%). .sup.1H-NMR
(200.15 MHz, CDCl.sub.3): .delta. 7.90 (d, 2H, J=8.0), 7.80-7.70
(m, 4H), 7.58-7.39 (m, 3H), 7.32 (d, 2H, J=8.4), 6.92 (d, 3H,
J=9.1), 4.13 (t, 2H, J=6.2), 4.02 (dd, 1H, J=7.3, 4.4), 3.38 (s,
3H), 3.20-3.00 (m, 4H), 2.25 (qn, 2H, J=6.2).
EXAMPLE 56
[0825]
(2S)-2-Methoxy-3-{4-[4-(4-phenoxy-phenoxy)-butyryl]-phenyl}-propion-
ic acid 110
[0826] Step A
[0827]
2S)-3-{4-[4-(4-phenoxy-phenoxy)-butyryl]-phenyl}-2-methoxy-propioni-
c acid ethyl ester 111
[0828]
(2S)-2-Methoxy-3-{4-[4-(4-phenoxy-phenoxy)-but-1-ynyl]-phenyl}-prop-
ionic acid ethyl ester (0.17 mmol) from Example 41, was dissolved
in 4 ml of methanol. To this solution was added 3 ml of a solution
of 0.075 g of mercury (II) oxide in 12 mL of 4% sulfuric acid. The
mixture was stirred at 55.degree. C. for 3 hour, cooled to room
temperature, and diluted with 20 mL saturated NaHCO.sub.3 solution.
The mixture was extracted with of dichloromethane (4.times.20 mL),
and the combined organic layers were dried (MgSO.sub.4), and
concentrated. The residue was purified by silica gel chromatography
(silica gel, hexanes/ethyl acetate 3:1) to give a yellow oil.
[0829] Step B
[0830]
(2S)-2-Methoxy-3-{4-[4-(4-phenoxy-phenoxy)-butyryl]-phenyl}-propion-
ic acid
[0831] The title compound was prepared from
(2S)-3-{4-[4-(4-phenoxy-phenox-
y)-butyryl]phenyl}-2-methoxy-propionic acid ethyl ester via the
standard hydrolysis procedure C. MS (ES) for
C.sub.28H.sub.26O.sub.6 [M+H].sup.+: 435.2.
EXAMPLE 57
[0832]
(2S)-3-[4-(Biphenyl-4-yloxy)-butyryl-phenyl]-2-methoxy-propionic
acid 112
[0833] Step A
[0834]
(2S)-3-{4-[4-(4-phenylphenoxy)-butyryl]-phenyl}-2-methoxy-propionic
acid ethyl ester 113
[0835]
(2S)-3-{4-[4-(Biphenyl-4-yloxy)-but-1-ynyl]-phenyl}-2-methoxy-propi-
onic acid ethyl ester (0.17 mmol) from Example 40, Step C, was
dissolved in 4 ml of methanol. To this solution was added 3 ml of a
solution of 0.075 g of mercury (II) oxide in 12 mL of 4% sulfuric
acid. The mixture was stirred at 55.degree. C. for 3 hours, cooled
to room temperature, and diluted with 20 mL saturated NaHCO.sub.3
solution. The mixture was extracted with of dichloromethane
(4.times.20 mL), and the combined organic layers were dried
(MgSO.sub.4), and concentrated. The residue was purified by silica
gel chromatography (silica gel, hexanes/ethyl acetate 3:1) to give
a yellow oil.
[0836] Step B
[0837]
(2S)-3-[4-(Biphenyl-4-yloxy)-butyryl-phenyl]-2-methoxy-propionic
acid
[0838] The title compound was prepared from
(2S)-3-{4-[4-(4-phenylphenoxy)-
-butyryl]-phenyl}-2-methoxy-propionic acid ethyl ester via the
standard hydrolysis procedure C. MS (ES) for
C.sub.26H.sub.26O.sub.5 [M+H].sup.+: 419.2.
EXAMPLE 58
[0839]
(2S)-3-{4-[6-(Biphenyl-4-yloxy)-hexanoyl]-phenyl}-2-methoxy-propion-
ic acid 114
[0840] A solution of triphenylphosphine (0.474 g, 1.8 mmol) in 50
mL of dry THF was treated at 0.degree. C. with
diethylazodicarboxylate (1.8 mmol) and stirred for 20 min. A
solution of 3-[4-(6-Hydroxy-hex-1-ynyl)-p-
henyl]-2-methoxy-propionic acid ethyl ester (Example 49, Step A)
(0.365 g, 1.2 mmol) and 4-phenylphenol (0.307 g, 1.8 mmol) in 10 mL
of dry THF was added, and the mixture was stirred at room
temperature overnight. The mixture was concentrated under vacuum
and purified by silica gel chromatography (silica gel,
hexanes/ethyl acetate 10:1 to 3:1). Fractions with R.sub.fs 0.48
and 0.45 (hexanes/ethyl acetate 2:1) corresponding to the coupled
compound and starting phenol, respectively, were combined and
concentrated. The mixture was dissolved in 5 mL of methanol and was
treated with a mixture of 0-712 mg of mercury (II) oxide and 12 ml
of 4% sulfuric acid in water. The solution was stirred at
55.degree. C. for 3 hours, cooled to room temperature, diluted with
saturated aqueous NaHCO.sub.3 (20 mL), and extracted with
dichloromethane (4.times.20 mL). The combined organic layers were
washed with brine (20 mL), dried (MgSO.sub.4), and concentrated.
The residue was dissolved in 6 mL of methanol and 2 mL of 1N NaOH
and stirred for 2 hours. The methanol was evaporated under vacuum,
and the aqueous solution was diluted with brine (6 mL) and washed
with diethyl ether (3.times.15 mL). The aqueous layer was acidified
with 1N HCl (pH 1-2) and extracted with ethyl acetate (3.times.15
mL). The combined extracts were dried (MgSO.sub.4) and concentrated
to give the title compound. MS(ES) for
C.sub.28H.sub.30O.sub.5[M+H].sup.+: 447.2.
EXAMPLE 59
[0841]
(2S)-2-Methoxy-3-{4-[6-(4-phenoxy-phenoxy)-hexanoyl]-phenyl}-propio-
nic acid 115
[0842] A solution of triphenylphosphine (1.8 mmol) in 50 mL of dry
THF was treated at 0.degree. C. with diethylazodicarboxylate (1.8
mmol) and stirred for 20 min. A solution of
3-[4-(6-Hydroxy-hex-1-ynyl)-phenyl]-2-m- ethoxy-propionic acid
ethyl ester (Example 49, Step A) (1.2 mmol) and 4-phenoxyphenol
(1.8 mmol) in 10 mL of dry THF was added, and the mixture was
stirred at room temperature overnight. The mixture was concentrated
under vacuum and purified by silica gel chromatography (silica gel,
hexanes/ethyl acetate 10:1 to 3:1). Fractions with R.sub.fs 0.48
and 0.45 (hexanes/ethyl acetate 2:1) corresponding to the coupled
compound and starting phenol, respectively, were combined and
concentrated. The mixture was dissolved in 5 mL of methanol and was
treated with a mixture of 0.712 mg of mercury (II) oxide and 12 ml
of 4% sulfuric acid in water. The solution was stirred at
55.degree. C. for 3 hours, cooled to room temperature, diluted with
saturated aqueous NaHCO.sub.3 (20 mL), and extracted with
dichloromethane (4.times.20 mL). The combined organic layers were
washed with brine (20 mL), dried (MgSO.sub.4), and concentrated.
The residue was dissolved in 6 mL of methanol and 2 mL of 1N NaOH
and stirred for 2 hours. The methanol was evaporated under vacuum,
and the aqueous solution was diluted with brine (6 mL) and washed
with diethyl ether (3.times.15 mL). The aqueous layer was acidified
with 1N HCl (pH 1-2) and extracted with ethyl acetate (3.times.15
mL). The combined extracts were dried (MgSO.sub.4) and concentrated
to give the title compound. MS(ES) for
C.sub.28H.sub.30O.sub.6[M+H].sup.+: 463.2.
EXAMPLE 60
[0843]
(2S)-3-{4-[6-(4-Benzoyl-phenoxy)-hexanoyl]-phenyl}-2-methoxy-propio-
nic acid 116
[0844] A solution of triphenylphosphine (1.8 mmol) in 50 mL of dry
THF was treated at 0.degree. C. with diethylazodicarboxylate (1.8
mmol) and stirred for 20 min. A solution of
3-[4-(6-Hydroxy-hex-1-ynyl)-phenyl]-2-m- ethoxy-propionic acid
ethyl ester (Example 49, Step A) (1.2 mmol) and
4-phydroxybenzophenone (1.8 mmol) in 10 mL of dry THF was added,
and the mixture was stirred at room temperature overnight. The
mixture was concentrated under vacuum and purified by silica gel
chromatography (silica gel, hexanes/ethyl acetate 10:1 to 3:1).
Fractions with R.sub.fs 0.48 and 0.45 (hexanes/ethyl acetate 2:1)
corresponding to the coupled compound and starting phenol,
respectively, were combined and concentrated. The mixture was
dissolved in 5 mL of methanol and was treated with a mixture of
0.712 mg of mercury (II) oxide and 12 ml of 4% sulfuric acid in
water. The solution was stirred at 55.degree. C. for 3 hours,
cooled to room temperature, diluted with saturated aqueous
NaHCO.sub.3 (20 mL), and extracted with dichloromethane (4.times.20
mL). The combined organic layers were washed with brine (20 mL),
dried (MgSO.sub.4), and concentrated. The residue was dissolved in
6 mL of methanol and 2 mL of 1N NaOH and stirred for 2 hours. The
methanol was evaporated under vacuum, and the aqueous solution was
diluted with brine (6 mL) and washed with diethyl ether (3.times.15
mL). The aqueous layer was acidified with 1N HCl (pH 1-2) and
extracted with ethyl acetate (3.times.15 mL). The combined extracts
were dried (MgSO.sub.4) and concentrated to give the title
compound. MS(ES) for C.sub.29H.sub.30O.sub.6[M+H].sup.+: 475.2.
EXAMPLE 61
[0845]
(2S)-3-{4-[5-(Biphenyl-4-yloxy)-1-hydroxyimino-pentyl]-phenyl}-2-me-
thoxy-propionic acid 117
[0846]
(2S)-3-{4-[5-(Biphenyl-4-yloxy)-pentanoyl]-phenyl}-2-methoxy-propio-
nic acid from Example 52, (1 eq) was mixed with Hydroxylamine
chlorydrate (4 eq), pyrydine (10 eq) and Ethanol (2 ml) and the
mixture reaction was stirred overnight. The ethanol was evaporated
under vacuo and HCl 0.5% was added to the residue to pH=3.
Extracted with Ethyl Acetate and concentrated to give the title
product as a mixture of two oximes. MS(ES) for
C.sub.27H.sub.29NO.sub.5 [M+H].sup.+: 448.2.2, [M-H].sup.-:
446.2.
EXAMPLE 62
[0847]
(2S,1'R*,(2S)*)-3-(4-{2'-[4-(4-(Fluoro-benzoyl)-phenoxy]-cyclopenty-
loxy}-phenyl)-2-methoxy-propionic acid 118
[0848] Step A
[0849] cis-2-(tert-Butyl-dimethyl-silanyloxy)-cyclopentanol 119
[0850] The title compound was prepared from
meso-1,2-cyclopentanediol via the Standard Procedure D for the
monoprotection of diols. The residue was purified by silica gel
chromatography (hexanes/ethyl 3:1, R.sub.f0.55) (50%). .sup.1H-NMR
(200.15 MHz, CDCl.sub.3): .delta. 4.04 (dt, 1H, J=4.6, 6.2),
3.95-3.89 (m, 1H), 2.59 (d, 1H, J=3.8), 1.88-1.49 (m, 6H), 0.91 (s,
9H), 0.09 (s, 6H).
[0851] Step B
[0852] (2S,1'R,2'R)
3-[4-(2'-Hydroxy-cyclopentyloxy)-phenyl]-2-methoxy-pro- pionic acid
ethyl ester 120
[0853] A solution of triphenylphosphine (0.634 g, 2.23 mmol) in 15
mL of dry THF was treated, at 0.degree. C. with
diethylazodicarboxylate (0.368 mL, 0.2.45 mmol) and stirred for 20
min. A solution of (2S)-2-methoxy-3-hydroxyphenylpropionic acid
ethyl (0.5 g, 2.23 mmol) and
cis-2-(tert-butyl-dimethyl-silanyloxy)cyclopentanol (0.531 g, 0.245
mmol) min 5 mL of dry THF was added to the solution, and the
mixture was stirred at room temperature overnight. The mixture was
concentrated under vacuum and the residue was purified by silica
gel chromatography (silica gel, hexanes/ethyl acetate 6:1).
Fraction with R.sub.fs 0.55 (hexanes/ethyl acetate 3:1)
corresponding to the coupled compound and starting phenol,
respectively, were collected and concentrated. The residue was
dissolved in 4 mL of TB, and tetrabutylammonium fluoride (2.23 mL,
1 M in THF) was added. The solution was stirred for 2 hours at room
temperature, diluted with 30 mL of diethyl ether, and washed with
1N HCl (2.times.20 mL). The organic solution was dried (MgSO.sub.4)
and concentrated. The residue was purified by silica gel
chromatography (silica gel, hexanes/ethyl acetate 3:1, R.sub.f 0.9)
to the product (60%). .sup.1H-NMR (200.15 MHz, CDCl.sub.3): .delta.
7.11 (d, 2H, J=8.6), 6.80 (d, 2H, J=8.9), 4.43-4.40 (m, 1H),
4.23-4.12 (m, 4H); 3.90 (dd, 1H, J=7.0, 5.9); 3.35 (s, 3H); 2.95
(d, 2H, J=6.7), 2.16-1.60 (m, 6H), 1.22 (t, 3H, J=7.0), 0.88 (s,
9H), 0.05 (d, 3H, J=2.2).
[0854] Step C
[0855] (2S,1'R*,2'S*)
3-(4-{2'-[4-(4-Fluoro-benzoyl)-phenoxy]-cyclopentylo-
xy}-phenyl)-2-methoxy-propionic acid
[0856] The title compound was prepared from
(2S,1'R,2'R)-3-[4-(2'-hydroxy--
cyclopentyloxy)-phenyl]-2-methoxy-propionic acid ethyl ester and
4-fluoro-4-hydroxybenzophenone via the Standard Procedure A.
.sup.1H-NMR (200.15 MHz, CDCl.sub.3): .delta. 7.82-7.67 (m, 4H),
7.18-7.06 (m, 4H), 6.93 (d, 2H, J=8.9), 6.76 (d, 2H, J=8.6),
4.88-4.74 (m, 2H), 3.97-3.94 (m, 1H), 3.39 (s, 3H); 3.09-2.89 (m,
2H); 2.23-1.98 (m, 6H). MS (ES) for C.sub.28H.sub.27FO.sub.6
[M+H].sup.+: 479.2, [M+Na].sup.+: 501.2.
EXAMPLE 63
[0857]
(2S)-(1'R,3'R)-2-Methoxy-3-{4-[1',3'-dimethyl-3-(4-phenoxy-phenoxy)-
-propoxy]-phenyl}-propionic acid 121
[0858] Step A
[0859] (2S,4S)-4-(tert-Butyl-dimethyl-silanyloxy)-pentan-2-ol
122
[0860] The title compound was prepared starting from
(2S,4S)pentanediol using the Standard Procedure D. MS (ES) for
C.sub.11H.sub.26O.sub.2Si [M+H].sub.+: 219.2.
[0861] Step B
[0862]
(2S)-(1'R,3'S)-3-{4-[3'-(tert-Butyl-dimethyl-silanloxy)-1'-methyl-b-
utoxy]-phenyl}-2-methoxy-propionic acid ethyl ester 123
[0863] The title compound was prepared using the Standard Procedure
for the Mitsounobu coupling B to give the product.
[0864] Step C
[0865]
(2S)-(1'R,3'S)-3-[4-(3'-Hydroxy-1'-methyl-butoxy)-phenyl]-2-methoxy-
-propionic acid methyl ester 124
[0866] The title compound was prepared folowing the Standard
Procedure E to give the product. MS (ES) for
C.sub.17H.sub.26O.sub.5 [M+H].sup.+: 328.2.
[0867] Step D
[0868]
(2S)-(1'R,2'R)-2-Methoxy-3-{4-[1'-methyl]-3'-(4-phenoxy-phenoxy)-bu-
toxy]-phenyl}-propionic acid ethyl ester 125
[0869] The title compound was prepared following the Standard
Mitsounobu coupling procedure B to give the corresponding product.
MS (ES) for C.sub.29H.sub.34O.sub.6 [M+NH.sub.4].sup.+: 496.2.
[0870] Step E
[0871]
(2S)-(1'R,3'R)-2-Methoxy-3-{4-[1',3'-dimethyl-3-(4-phenoxy-phenoxy)-
-propoxyl]-phenyl}-propionic acid
[0872] The title compound was prepared by the Standard hydrolysis
procedure C of the compound from Step D to give the final compound
as a gummy solid. .sup.1H-NMR (CDCl.sub.3, 200.15 MHz): 7.32-7.24
(m, 2H), 7.10-6.75 (m, 11H), 4.70-4.50 (m, 2H), 3.95 (dd, 1H,
J=7.3, 4.3), 3.36 (s, 3H), 3.06 (dd, 1H, J=14.5, 4.6), 2.92 (dd,
1H, J=14.2, 7.5), 1.96 (dd, 2H, J=6.7, 5.4), 1.31 (d, 6H,
J=6.2).ppm. MS(ES) for C.sub.27H.sub.30O.sub.6 [M+NH.sub.4].sup.+:
468.2, [M-H].sup.-: 449.2.
EXAMPLE 64
[0873]
(2S)-(1'R,3'R)-3-{4-[3-(4-Benzoylphenoxy)-1,3'-dimethylpropoxyl]-ph-
enyl}2-methoxy-propionic acid 126
[0874] The title compound was prepared in a manner analogous that
Example 63, starting from the (2S,4S)-pentanediol to give the final
compound. .sup.1H-NMR (CDCl.sub.3, 200.15 MHz): 9.24 (s, 1H), 7.75
(t, 1H, J=1.6), 7.70 (t, 1H, J=1.9), 7.69 (dd, 2H, J=12.6, 2.2),
7.59-7.40 (m, 3H), 7.04 (d, 2H, J=8.6), 6.85 (d, 2H, J=9.1), 6.69
(d, 2H, J=8.9), 4.87-4.72 (m, 1H), 4.62-4.47 (m, 1H), 3.94 (dd, 1H,
J=7.0, 5.6), 3.37 (s, 3H), 3.05-2.86 (m, 2H), 1.99 (dd, 2H, J=6.7,
5.4), 1.36 (d, 3H, J=6.2), 1.30 (d, 3H, J=6.2).
EXAMPLE 65
[0875]
(2S)-(1'S,3')-2-Methoxy-3-{4-[1',3'-dimethyl-3-(4-phenoxy-phenoxy)--
propoxyl]-phenyl}-propionic acid 127
[0876] The title compound was prepared in a manner analogous that
Example 63, starting from the (2R,4R)-pentanediol to give the final
compound. .sup.1H-NMR (CDCl.sub.3, 200.15 MHz): 7.33-7.25 (m, 2H),
7.12-6.76 (m, 11H), 4.71-4.49 (m, 2H), 3.95 (dd, 1H, J=7.5, 4.6),
3.36 (s, 3H), 3.05 (dd, 1H, J=14.5, 4.6), 2.93 (dd, 1H, J=14.2,
7.5), 1.96 (dd, 2H, J=7.0, 5.7), 1.31 (d, 6H, J=6.2). MS(ES) for
C.sub.27H.sub.30O.sub.6 [M+NH.sub.4].sup.+: 468.2, [M-H].sup.-:
449.2.
EXAMPLE 66
[0877]
(2S)-(1'S,3'S)-3-{4-[3-(4-Benzoylphenoxy-1',3'-dimethylpropoxyl]-ph-
enyl}2-methoxy-propionic acid 128
[0878] The title compound was prepared in a manner analogous that
Example 63, starting from the (2R,4R)-pentanediol to give the final
compound .sup.1H-NMR (CDCl.sub.3, 200.15 MHz): 7.76-7.41 (m, 7H),
7.02 (d, 2H, J=8.6), 6.83 (d, 2H, J=8.9), 6.67 (d, 2H, J=8.6), 4.78
(dd, 1H, J=12.1, 6.2), 4.63-4.47 (m, 1H), 3.99 (dd, 1H, J=6.2,
4.8), 3.41 (s, 3H), 3.08-2.87 (m, 2H), 2.00 (dd, 2H, J=5.6, 12.4),
1.33 (dd, 6H, J=11.6, 6.2). MS(ES) for C.sub.28H.sub.30O.sub.6
[M+H].sup.+: 463.2, [M-H].sup.-: 461.3.
EXAMPLE 67
[0879]
(2S)-(1'R,2'R)-2-Methoxy-3-{4-[1',2'-dimethyl-(4-phenoxy-phenoxy)-e-
thoxyl]-phenyl}-propionic acid 129
[0880] The title compound was prepared in a manner analogous that
63, starting from the (2S,3S)-butane-2,3-diol to give the final
compound. .sup.1H-NMR (CDCl.sub.3, 200.15 MHz): 7.94 (m, 1H),
7.34-7.26 (m, 3H), 7.17-6.83 (m, 10H), 4.59-4.38 (m, 2H), 3.98 (dd,
1H, J=7.5, 4.6), 3.39 (s, 3H), 3.08 (dd, 1H, J=14.2, 4.3), 2.95
(dd, 1H, J=14.2, 7.5), 1.36 (d, 6H, J=6.2). MS(ES) for
C.sub.26H.sub.28O.sub.6 [M+NH.sub.4].sup.+: 454.2, [M-H].sup.-:
435.2.
EXAMPLE 68
[0881]
(2S)-(1'R,2'R)-3-{4-[1-(4-Benzoylphenoxy)-1',2'-dimethyl-ethoxyl]-p-
henyl}-2-methoxypropionic acid 130
[0882] The title compound was prepared in a manner analogous that
Example 63, starting from the (2S,3S)butane-2,3-diol to give the
final compound. .sup.1H-NMR (CDCl.sub.3, 200.15 MHz): 7.77 (t, 3H,
J=8.9), 7.74 (s, 1H), 7.60-7.42 (m, 3H), 7.14 (d, 2H, J=8.6), 6.96
(d, 2H, J=8.9), 6.84 (d, 2H, J=8.9), 4.72-4.60 (m, 1H), 4.59-4.47
(m, 1H), 3.98 (dd, 1H, J=7.5, 4.6), 3.39 (s, 3H), 3.08 (dd, 1H,
J=14.5, 4.6), 2.95 (dd, 1H, J=14.2, 7.3), 1.42 (d, 3H, J=6.2), 1.37
(d, 3H, J=6.2). MS(ES) for C.sub.27H.sub.28O.sub.6 [M+H].sup.+:
449.2, [M-H].sup.-: 447.2.
EXAMPLE 69
[0883]
(2S)-(1'S,4'S)-2-Methoxy-3-{4-[1'-methyl-4'-(4-phenoxy-phenoxy)-pen-
tyloxy]-phenyl}-propionic acid 131
[0884] The title compound was prepared in a manner analogous that
Example 63, starting from the (2R,5R)-hexane-2,5-diol to give the
final compound. .sup.1H-NMR (200.15 MHz, CDCl.sub.3): 7.3-7.2 (m,
2H), 7.14 (d, 2H, J=8.6), 7.1-6.8 (m, 9H), 4.4-4.3 (m, 2H), 3.97
(dd, 1H, J=7.6, 4.4), 3.39 (s, 3H), 3.08 (dd, 1H, J=14.2, 4.4),
2.95 (dd, 1H, J=14.4, 7.6), 2.0-1.7 (m, 4H), 1.31 (d, 6H, J=6.2)
ppm.
EXAMPLE 70
[0885]
(2S)-(1'S,4'S)-3-{4-[4-(4-Benzoyl-phenoxy)-1-methyl-pentyloxy]-phen-
yl}-2-methoxy-propionic acid 132
[0886] The title compound was prepared in a manner analogous that
Example 63, starting from the (2R,5R)-hexane-2,5-diol to give the
final compound. .sup.1H-NMR (200.15 MHz, CDCl.sub.3): 7.8-7.7 (m,
4H), 7.6-7.5 (m, 3H), 7.13 (d, 2H, J=8.6), 6.90 (dd, 2H, J=7.0,
2.0), 6.79 (d, 2H, J=8.6), 4.51 (c, 1H, J=6.0), 4.35 (c, 1H,
J=6.0), 3.98 (dd, 1H, J=7.2, 4.8), 3.39 (s, 3H), 3.08 (dd, 1H,
J=14.4, 4.8), 2.95 (dd, 1H, J=14.4, 7.2), 2.0-1.7 (m, 4H), 1.35 (d,
3H, J=6.0), 1.30 (d, 3H, J=6.0) ppm.
EXAMPLE 71
[0887]
(2S)-(1'R,4'R)-2-Methoxy-3-{4-[1'-methyl-4'-(4-phenoxy-phenoxy)-pen-
tyloxy]-phenyl}-propionic acid 133
[0888] The title compound was prepared in a manner analogous that
Example 63, starting from the (2S,5S)-hexane-2,5-diol to give the
final compound. .sup.1H-NMR (200.15 MHz, CDCl.sub.3). 7.3-7.2 (m,
2H), 7.14 (d, 2H, J=8.4), 7.1-6.7 (m, 9H), 4.4-4.2 (m, 2H), 3.96
(dd, 1H, J=7.4, 4.4), 3.37 (s, 3H), 3.07 (dd, 1H, J=14.4, 4.4),
2.93 (dd, 1H, J=14.4, 7.4), 2.0-1.6 (m, 4H), 1.30 (d, 6H, J=6.0)
ppm.
EXAMPLE 72
[0889]
(2S)-(1'R,4'R)-3-{4-[4-(4-Benzoyl-phenoxy)-1-methyl-pentyloxy]-phen-
yl}-2-methoxy-propionic acid 134
[0890] The title compound was prepared in a manner analogous that
Example 63, starting from the (2S,55)-hexane-2,5-diol to give the
final compound. .sup.1H-NMR (200.15 MHz, CDCl.sub.3): 7.8-7.5 (m,
3H), 7.5-7.4 (m, 3H), 7.06 (d, 2H, J=5.6), 6.82 (d, 2H, J=6.0),
6.71 (d, 2H, J=5.8), 4.44 (c, 1H, J=3.6), 4.28 (c, 1H, J=3.6), 3.88
(dd, 1H, J=9.6, 2.8), 3.29 (s, 3H), 2.98 (dd, 1H, J=9.6, 2.8), 2.86
(dd, 1H, J=9.6, 5.0), 1.9-1.6 (m, 4H), 1.27 (d, 3H, J=4.0), 1.21
(d, 3H, J=4.0) ppm.
EXAMPLE 73
[0891]
(2S)-(1'S,2'S)-2-Methoxy-3-{4-[1',2'-dimethyl-(4-phenoxy-phenoxy)-e-
thoxy]-phenyl}-propionic acid 135
[0892] Step A
[0893] (2R,3S)-3-(4-phenoxy-phenoxy)-butan-2-ol 136
[0894] A solution of (2R,3R)-butane-2,3-diol was monoprotected with
tert-butyldimethylsilyl chloride using the Standard Procedure D,
after purification by chromatography, the compound was coupling
with 4-phenoxyphenol using Standard Procedure B (in THF) and
deprotected with tetrabutylamonium fluoride as Standard Procedure E
to give the title compound as an oil. MS (ES) for
C.sub.16H.sub.18O.sub.3 [M+NH.sub.4].sup.+: 276.2.
[0895] Step B
[0896] (1R,2S)-Toluene-4-sulfonic acid
1-methyl-2-(4-phenoxy-phenoxy)-prop- yl ester 137
[0897] To a solution of compound from Step A (1 eq) in neat
pyridine, p-Toluenesulfonic chloride (1.5 eq) was added and the
mixture reaction was stirred at room temperature over two days. The
reaction was quenched with HCl 1N and extracted with ethyl acetate
and washing the organic layers with brine (3 times). The organic
layers were dry and concentrated in vacuo to give a residue which
was purified by silica gel chromatography to give the title
product. MS (ES) for C.sub.23H.sub.24O.sub.5S [M+NH.sub.4].sup.+:
430.1.
[0898] Step C
[0899]
(2S)-(1'S,2'S)-2-Methoxy-3-{4-[1',2'-dimethyl-(4-phenoxy-phenoxy)-e-
thoxyl]-phenyl}-propionic acid ethyl ester 138
[0900] A solution of (1R,2S)-Toluene-4-sulfonic acid
1-methyl-2-(4-phenoxy-phenoxy)-propyl ester from above Step (1 eq),
potassium carbonate (3 eq) and
2S)-3-(4-Hydroxy-phenyl)-2-methoxy-propion- ic acid ethyl ester (1
eq) in acetonitrile was refluxed overnight. The solution was
evaporated to dryness and chromatographied to get the title
compound. MS (ES) for C.sub.27H.sub.30O.sub.7 [M+NH.sub.4].sup.+:
482.4.
[0901] Step D
[0902]
(2S)-(1'S,2'S)-2-Methoxy-3-{4-[1',2'-dimethyl-(4-phenoxy-phenoxy)-e-
thoxyl]-phenyl}-propionic acid
[0903] The title compound was prepared using the Standard
hydrolysis Procedure C to give the final product as an oil.
.sup.1H-NMR (CDCl.sub.3, 200.15 MHz): 7.34-7.26 (m, 3H), 7.16-6.83
(m, 10H), 4.58-4.41 (m, 2H), 3.98 (dd, 1H, J=7.3, 4.3), 3.39 (s,
3H), 3.14-2.89 (m, 2H), 1.35 (d, 6H, J=6.2). MS(ES) for
C.sub.26H.sub.28O.sub.6 [M+NH.sub.4].sup.+: 454.3, [M-H].:
435.1.
EXAMPLE 74
[0904]
(2S)-2-Methoxy-{4-[2-methylen-3-(4-phenoxy-phenoxy)-propoxyl]-pheny-
l}-propionic acid 139
[0905] Step A
[0906] 2-(4-phenoxy-phenoxymethyl)-prop-2-en-1-ol 140
[0907] A solution of triphenylphosphine (1 eq) in toluene at
0.degree. C. was treated with diethylazodicarboxylate (1 eq) and
stirred for 20 min. Then a solution of 4-pehoxyphenol and
2-Methylene-propane-1,3-diol in toluene was added to the solution
and the mixture reaction was stirred overnight. Concentrated to
dryness and chromatographied to give the title compound.
[0908] Step B
[0909]
(2S)-2-Methoxy-{4-[2-methylen-3-(4-phenoxy-phenoxy)-propoxyl]-pheny-
l}-propionic acid ethyl ester 141
[0910] The title compound was prepared using Standard Mitsounobu
coupling conditions B.
[0911] Step C
[0912]
(2S)-2-Methoxy-{4-[2-methylen-3-(4-phenoxy-phenoxy)-propoxy]-phenyl-
}-propionic acid
[0913] The title compound was prepared by using the Standard
Procedure for hydrolysis C to give the final product as an oil.
.sup.1H-NMR (CDCl.sub.3, 200.15 MHz): 8.09 (s, 1H), 7.34-6.86 (m,
13H), 5.41 (s, 2H), 4.62 (s, 4H), 3.98 (dd, 1H, J=7.5, 4.6), 3.40
(s, 3H), 3.09 (dd, 1H, J=14.5, 4.6), 2.97 (dd, 1H, J=14.5,
7.5).
EXAMPLE 75
[0914]
(2S)-2-Methoxy-{4-[2-oxo-3-(4-phenoxy-phenoxy)-propoxy]-phenyl}-pro-
pionic acid 142
[0915] A solution of
(2S)-2-Methoxy-{4-[2-methylen-3-(4-phenoxy-phenoxy)-p-
ropoxyl]-phenyl}-propionic acid from Example 74, in dichloromethane
at -78.degree. C. was treated with ozone until the solution turned
blue. Washed with brine, dry and concentrated to dryness to give
the title compound. .sup.1H-NMR (CDCl.sub.3, 200.15 MHz): 7.35-6.83
(m, 13H), 4.86 (d, 4H, J=3.0), 3.98 (dd, 1H, J=7.3, 4.3), 3.40 (s,
3H), 3.10 (dd, 1H, J=14.2, 4.0), 2.97 (dd, 1H, J=14.5, 7.3). MS(ES)
for C.sub.25H.sub.24O.sub.7 [M+NH.sub.4].sup.+: 454.2, [M-H].sup.-:
435.2.
EXAMPLE 76
[0916]
(2S)-2-Methoxy-3-{4-[3-(4-phenoxy-phenoxymethyl)-benzyloxy]-phenyl}-
-propionic acid 143
[0917] The title compound was prepared in a manner analogous that
Example 74, starting from (3-Hydroxymethyl-phenyl)-ethanol to give
the final compound. .sup.1H-NMR (200.15 MHz, CDCl.sub.3): 7.50 (s,
1H), 7.40 (s, 2H), 7.28 (d, 2H, J=8.6), 7.17 (d, 2H, J=8.6),
7.1-6.9 (m, 10H), 5.06 (s, 4H), 3.99 (dd, 1H, J=7.2, 4.4), 3.40 (s,
3H), 3.10 (dd, 1H, J=14.4, 4.6), 2.97 (dd, 1H, J=14.2, 7.4)
ppm.
EXAMPLE 77
[0918]
(2S)-2-Methoxy-3-{4-[2-(4-phenoxy-phenoxymethyl)-benzyloxy]-phenyl}-
-propionic acid 144
[0919] The title compound was prepared in a manner analogous that
Example 63, starting from (2-Hydroxymethyl-phenyl)-methanol to give
the final compound. .sup.1H-NMR (200.15 MHz, CDCl.sub.3): 7.5-7.4
(m, 2H), 7.4-7.3 (m, 2H), 7.28 (d, 2H, J=8.0), 7.16 (d, 2H, J=8.6),
7.16.9 (m, 9H), 5.14 (s, 4H), 3.95 (dd, 1H, J=7.4, 4.6), 3.37 (s,
3H), 3.07 (dd, 1H, J=14.2, 4.4), 2.94 (dd, 1H, J=14.2, 7.6)
ppm.
EXAMPLE 78
[0920]
(2S)-2-Methoxy-3-{4-[3-(4-phenoxy-phenoxy-phenoxy]-phenyl}-propioni-
c acid 145
[0921] Step A
[0922] (2S)-3-[4-(3-Bromo-phenoxy)-phenyl]-2-methoxy-propionic acid
ethyl ester 146
[0923] An ovendried resealable Schlenk tube was fitted with a
rubber septum and was cooled to room temperature under N.sub.2
purge. The tube was charge with Pd(OAc).sub.2(2.0 mol %),
2-(ditert-butylphosphino)biphen- yl (0.03 eq), potassium phosphate
(2 eq), 1,3-dibromobenzene (1 eq) and
(2S)-3-(4-Hydroxy-phenyl)-2-methoxy-propionic acid ethyl ester (1.2
eq). The tube was capped with the septum and purged with N2, and
then toluene was added through the septum. The tube was sealed with
a teflon screwcap, and the reaction mixture was stirred at
100.degree. C. for 16 hours. The solvent was removed and the
residue was purified by chromatography to afford the title
compound.
[0924] Step B
[0925]
(2S)-2-Methoxy-3-{4-[3-(phenoxy-phenoxy)-phenoxy]-phenyl}-propionic
acid ethyl ester 147
[0926] The title compound was porcepared using the same coupling
procedure described above for Step A with 4-phenoxyphenol and
(2S)-3-[4-(3-Bromo-phenoxy)-phenyl]-2-methoxy-propionic acid ethyl
ester.
[0927] Step C
[0928]
(2S)-2-Methoxy-3-{4-[3-(4-phenoxy-phenoxy)-phenoxy]-phenyl}-propion-
ic acid
[0929] The title compound was prepared from Step B by using Standar
Procedure for the hydrolysis C. MS (ES) for C.sub.28H.sub.24O.sub.6
[M+Na].sup.+: 479.
EXAMPLE 79
[0930]
(2S)-3-[3'-(3-Benzoyl-phenoxymethyl)-biphenyl-4-yl-2-methoxy-propio-
nic acid 148
[0931] Step A
[0932] (2S)-3-(3'-Hydroxymethyl-biphenyl-4-yl)-2-methoxy-propionic
acid ethyl ester 149
[0933] A solution of (2S)
2-Methoxy-3-(4-trifluoromethanesulfonyloxy-pheny- l)-propionic acid
ethyl ester (Example 1, Step A) (150 mg, 0.42 mmol), 3-formylphenyl
boronic acid (126 mg, 0.842 mmol) and
tetrakis(triphenylphosphine)-palladium (0) (15 mg, 0.013 mmol) in
11 ml of a mixture 20:1 toluene/ethanol together with 2 ml of a 2N
Na.sub.2CO.sub.3 was heated to 120.degree. C. for 6 hours under
nitrogen atmosphere. The reaction mixture was cooled to room
temperature and dilute with EtOAc (20 ml). It was washed with
H.sub.2O (3.times.5 ml) and sodium tartrate (3.times.5 ml). The
combined organic layers were dried (MgSO.sub.4), filtered and
concentrated in vacuum. The resultant crude was purified by column
chromatography (silica gel, hexanes/ethyl acetate 3:1). Fractions
corresponding to the desired compound (R.sub.f: 0.27) were
collected and concentrate to dryness. The product was dissolved in
MeOH cooled at 0.degree. C., and sodium borohydride (3 eq) was
added. The solution was stirred for 1 h. and then diluted with
Ethyl-acetate (20 ml). It was washed with H.sub.2O (3.times.5 ml)
and NaHCO.sub.3 (3.times.5 ml). The combined organic layers were
dried (MgSO.sub.4), filtered and concentrated in vacuum. The
resultant crude was purified by column (silica gel, hexanes/ethyl
acetate 2:1). Obtained a colorless oil (60 mg, 45%). .sup.1H-NMR
(200.15 MHz, CDCl.sub.3): .delta. 7.55-7.23 (m, 8H), 4.71 (s, 2H),
4.18 (q, 2H, J=7.0), 3.93 (dd, 1H, J=7.3, 5.6), 3.35 (s, 3H), 3.05
(s, 1H), 3.02 (s, 1H), 1.25 (t, 3H, J=7.25)
[0934] Step B
[0935]
(2S)-3-[3'-(3-Benzoyl-phenoxymethyl)-biphenyl-4-yl]-2-methoxy-propi-
onic acid
[0936] The title compound was prepared from
(2S)-3-(3'-Hydroxymethyl-biphe- nyl-4-yl)-2-methoxy-propionic acid
ethyl ester (Step A) and 4-Hydroxybenzophenone via the standard
Mitsunobu coupling-hydrolisis procedure (Standard Procedure A) to
produce a white oily solid. .sup.1H-NMR (200.15 MHz, CDCl.sub.3):
.delta. 7.83-7.33 (m, 15H), 7.03 (d, 2H, J=8.1), 5.17 (s, 2H), 4.07
(dd, 1H, J=6.9, 3.7), 3.40 (s, 3H), 3.16 (dd, 1H, J=14.1, 3.6),
3.06 (dd, 1H, J=14.1, 7.0).
EXAMPLE 80
[0937]
(2S)-3-[4'-(4-Benzoyl-phenoxymethyl)-biphenyl-4-yl]-2-methoxy-propi-
onic acid 150
[0938] Step A
[0939] (2S)-3-(4'-Hydroxymethyl-biphenyl-4-yl)-2-methoxy-propionic
acid ethyl ester 151
[0940] A mixture of
(2S)-2-Methoxy-3-(4-trifluoromethanesulfonyloxy-phenyl- )-propionic
acid ethyl ester from Example 1, Step A (1 eq),
tetrakis(triphenylphosphine) palladium(0) (0.03 eq), sodium
carbonate (1.5 eq) and 4-hydroxymethylphenylboronic acid (2 eq) in
Toluene/Ethanol (20:1) was refluxed till the reaction is completed
by TLC. The mixture was diluted with ethyl acetate, extracted and
washed with water, NaHCO.sub.3, sodium tartrate and brine. The
organic layer was concentrated to dryness and chromatographied to
afford the title compound.
[0941] Step B
[0942]
(2S)-3-[4'-(4-Benzoyl-phenoxymethyl)-biphenyl-4-yl]-2-methoxy-propi-
onic acid
[0943] (2S)-3-(4'-Hydroxymethyl-biphenyl-4-yl)-2-methoxy-propionic
acid ethyl ester from Step A, was treated with
4-hydroxybenzophenone under the standard Mitsunobu coupling
procedure B (THF). The product obtained after chromatography was
hydrolyzed using the Standard Procedure C to get the title
compound. .sup.1H-NMR (CDCl.sub.3, 200.15 MHz): 7.86-7.73 (m, 4H),
7.63-7.43 (m, 9H), 7.34-7.29 (m, 2H), 7.05 (d, 2H, J=9.1), 5.18 (s,
2H), 4.06 (dd, 1H, J=7.3, 4.0), 3.42 (s, 3H), 3.20 (dd, 1H, J=14.5,
4.0), 3.06 (dd, 1H, J=14.5, 7.3). MS (ES) for
C.sub.30H.sub.26O.sub.5 [M+H].sup.+: 467.2, [M+Na].sup.+:
489.2.
EXAMPLE 81
[0944]
(2S)-(1'R*,3'R*)3-{4-[3'-(Biphenyl-4-yloxy)-1'-cyclopentyloxy]-phen-
yl}-2-methoxy-propionic acid 152
[0945] Step A
[0946] (1RS,3RS)-3-(tert-Butyl-dimethyl-silanyloxy)-cyclopentanol
153
[0947] To a solution of rac-1,3-pentanediol (0.46 g, 4.5 mmol) in
23 mL of THF at 0.degree. C. was added sodium hydride (0.18 g, 4.5
mmol, 60% oil dispersion). The mixture was stirred at 0.degree. C.
for 1 h. Tert-butyldimethylsilyl chloride (0.678 g, 4.5 mmol) was
added, and the mixture was stirred overnight at room temperature.
The mixture compounds were concentrated and purified by silica gel
chromatography (silica gel, hexanes/ethyl acetate 3:1) to give
0.682 g, of the title compound trans and 0.157 g (6%) of the other
cis isomer (1R*,3S*)-3-(tert-Butyl-dimethyl-
-silanyloxy)-cyclopentanol. .sup.1H-NMR (200.15 MHz, CDCl.sub.3):
.delta. 4.48-4.36 (m, 2H), 2.19-1.89 (m, 2H), 1.85-1.79 (m, 2H),
1.58-1.46 (m, 2H), 0.89 (s, 9H), 0.04 (s, 6H).
[0948] Step B
[0949]
(1R*,3S*)-[3-(Biphenyl-4-yloxy)-cyclopentyloxy]-tert-butyl-dimethyl-
-silane 154
[0950] A solution of triphenylphosphine (0.195 g, 0.742 mmol) in 5
mL of dry THF was treated at 0.degree. C. with
diethylazodicarboxylate (0.117 mL, 0.742 mmol) and stirred for 20
min. A solution of
(1R*,3R*)-3-(tert-butyldimethylsilanyloxy)cyclopentanol (0.146 g,
0.675 mmol) and 4-phenyl phenol (0.126 g, 0.0.724 mmol) in 5 mL of
dry THF was added to the solution, and the mixture was stirred at
room temperature overnight. The solution was concentrated under
vacuum and purified by silica gel chromatography (silica gel,
hexanes/ethyl acetate 6:1, R.sub.f0.66). .sup.1H-NMR (200.15 MHz,
CDCl.sub.3): .delta. 7.58-7.29 (m, 7H); 6.93 (d, 2H, J=8.92),
4.76-4.65 (m, 1H), 4.32-4.21 (m, 1H), 2.38 (qn, 1H, J=7.0),
2.04-1.94 (m, 2H), 1.87-1.78 (m, 3H), 0.90 (s, 9H), 0.07 (s, 3H),
0.06 (s, 3H).
[0951] Step C
[0952] (1R*,3S*)-3-(Biphenyl-4-yloxy)-cyclopentanol 155
[0953]
(1R*,3S*)-[3-(Biphenyl-4-yloxy)-cyclopentyloxy]-tert-butyldimethyls-
ilane (0.25 g, 0.67 mmol) was dissolved in 2 mL of THF and
tetrabutylammonium fluoride (0.67 mL, 1M in THF) and stirred at
room temperature for 2 hours. The solution was diluted with 15 mL
of diethyl ether and washed with 1N HCl (2.times.15 mL). The
organic layer was dried (MgSO.sub.4) and concentrated. The residue
was purified by silica gel chromatography (silica gel,
hexanes/ethyl acetate 3:1, R.sub.f0.09) to give the product (100%).
.sup.1H-NMR (200.15 MHz, CDCl.sub.3): .delta. 7.58-7.26 (m, 7H),
6.95 (d, 2H, J=8.9), 4.92-4.84 (m, 1H), 4.40-4.38 (m, 1H),
2.18-1.92 (m, 7H).
[0954] Step D
[0955]
(2S)-(1'R*,2'R*)3-{4-[3-(Biphenyl-4-yloxy)-cyclopentyloxy]-phenyl}--
2-methoxy-propionic acid
[0956] The title compound was prepared from (1R*,3S*)
3-(Biphenyl-4-yloxy)-cyclopentanol and
(2S)-2-methoxy-3-hydroxyphenylprop- ionic acid ethyl ester via the
Standard Procedure A. Oily solid. .sup.1H-NMR (CDCl.sub.3, 200.15
MHz): .delta. 7.57-7.29 (m, 7H), 7.15 (d, 2H, J=8.6), 6.94 (d, 2H,
J=8.9), 6.81 (d, 2H, J=8.6), 4.99-4.91 (m, 2H), 3.99 (dd, 1H,
J=7.3, 4.6), 3.41 (s, 3H), 3.10 (dd, 1H, J=14.2, 4.6), 2.96 (dd,
1H, J=14.5, 7.3), 2.31 (t, 2H, J=4.8), 2.26-1.97 (m, 4H).
EXAMPLE 82
[0957]
(2S)-(1'R*,3S*)3-{4-[3'-(Biphenyl-4-yloxy)-1'-cyclopentyloxy]-pheny-
l}-2-methoxy-propionic acid 156
[0958] Step A
[0959] (1R*,3S*)-3-(tert-Butyl-dimethyl-silanyloxy)-cyclopentanol
157
[0960] The title compound was isolated from Example 81, Step A in a
6% yield.
[0961] Step B
[0962]
(2S)-(1'R*,3'S*)3-{4-[3'-(Biphenyl-4-yloxy)-1'-cyclopentyloxy]-phen-
yl}-2-methoxy-propionic acid
[0963] The title compound was prepared starting from compound from
Step A and following the same procedure as in Example 81, to give
the final product. MS (ES) for C.sub.27H.sub.28O.sub.5
[M+NH.sub.4].sup.+: 450.2, [M+Na].sup.+: 455.23.
EXAMPLE 83
[0964]
(2S)-(1'R*,3'R*)-2-Methoxy-3-{4-[3'-(4-phenoxy-phenoxy)-1'-cyclopen-
tyloxy]-phenyl}-propionic acid 158
[0965] Step A
[0966]
(2S)-(1R*,3S*)-3-{4-[3'-(tert-Butyl-dimethyl-silanyloxy)-1'-cyclope-
ntyloxy]-phenyl}-2-methoxy-propionic acid ethyl ester 159
[0967] A solution of triphenylphosphine (0.634 g, 2.23 mmol) in 15
mL of dry THF was treated at 0.degree. C. with
diethylazodicarboxylate (0.2.45 mmol) and stirred for 20 min. A
solution of (2S)-2-methoxy-3-hydroxypheny- lpropionic acid ethyl
(2.23 mmol) and 1R*,3R*-tert-butyldimethylsylyloxy-c- yclopentanol
(0.245 mmol) in 5 mL of dry THF was added to the solution, and the
mixture was stirred at room temperature overnight. The mixture was
concentrated under vacuum and the residue was purified by silica
gel chromatography.
[0968] Step B
[0969]
(2S)-(1R*,3S*)-3-[4-(3'-Hydroxy-1'-cyclopentyloxy)-phenyl]-2-methox-
y-propionic acid ethyl ester 160
[0970] The title compound was prepared folowing the Standard
Procedure E to give the product.
[0971] Step C
[0972]
(2S)-(1'R*,3'R*)-2-Methoxy-3-{4-[3'-(4-phenoxy-phenoxy)-1'-cyclopen-
tyloxy]-phenyl}-propionic acid
[0973]
(2S)-(1R*,3S*)-3-[4-(3'-Hydroxy-1'-cyclopentyloxy)-phenyl]-2-methox-
y-propionic acid ethyl ester from Step A, was treated with
4-phenoxyphenol under the standard Mitsounobu coupling procedure B
(THF). The product obtained after chromatography was hydrolyzed
using the standard hydrolysis procedure C to get the title
compound. .sup.1H-NMR (CDCl.sub.3, 200.15 MHz): 7.34-7.26 (m, 2H),
7.17-7.04 (m, 3H), 7.00-6.92 (m, 4H), 6.88-6.78 (m, 4H), 4.94-4.89
(m, 2H), 3.99 (dd, 1H, J=7.3, 4.3), 3.41 (s, 3H), 3.10 (dd, 1H,
J=14.2, 4.6), 2.96 (dd, 1H, J=14.2, 7.3), 2.28 (t, 2H, J=4.8),
2.21-1.89 (m, 4H). MS (ES) for C.sub.27H.sub.26O.sub.6
[M+NH.sub.4].sup.+: 466.2, [M+Na].sup.+: 471.2.
EXAMPLE 84
[0974]
(2S)-(1'R*,3'R*)-3-{4-[3-(4-Benzoyl-phenoxy)-cyclopentyloxy]-phenyl-
}-2-methoxy-propionic acid 161
[0975] The title compound was prepared as manner analogous in
Example 83, starting from
(1R*,3R*)-3-(tert-Butyl-dimethyl-silanyloxy)-cyclopentanol and
4-hydroxy nezophenone. .sup.1H-NMR (CDCl.sub.3, 200.15 MHz):
7.83-7.73 (m, 4H), 7.56-7.42 (m, 3H), 7.15 (d, 2H, J=8.3), 6.92
(dd, 2H, J=7.0, 1.9), 6.80 (d, 2H, J=8.6), 5.03-5.01 (m, 1H),
4.96-4.92 (m, 1H), 3.98 (dd, 1H, J=7.3, 4.6), 3.39 (s, 3H), 3.09
(dd, 1H, J=14.5, 4.6), 2.95 (dd, 1H, J=14.2, 7.3), 2.40-1.91 (m,
6H). MS (ES) for C.sub.28H.sub.28O.sub.6 [M+H].sup.+: 461.2,
[M+Na].sup.+: 483.2.
EXAMPLE 85
[0976]
(2S)-(1'R*,3'R*)-2-Methoxy-3-{4-[3-(4-phenylacetyl-phenoxy)-cyclope-
ntyloxy]-phenyl}-propionic acid 162
[0977] The title compound was prepared as manner analogous in
Example 83, starting from
(1R*,3R*)-3-(tert-Butyl-dimethyl-silanyloxy)-cyclopentanol and
1-(4-Hydroxy-phenyl)-2-phenyl-ethanone. MS (ES) for
C.sub.29H.sub.30O.sub.6 [M+H].sup.+: 475.2, [+Na].sup.+: 497.2.
.sup.1H-NMR (CDCl.sub.3, 200.15 MHz): 7.97 (d, 2H, J=8.9),
7.32-7.23 (m, 5H); 7.15 (d, 2H, J=8.6), 6.91-6.77 (m, 4H),
5.01-4.91 (m, 2H), 4.22 (s, 2H), 3.98 (dd, 1H, J=7.3, 4.6), 3.40
(s, 3H), 3.09 (dd, 1H, J=14.2, 4.6), 2.96 (dd, 1H, J=14.5, 7.3),
2.33-1.92 (m, 6H).
EXAMPLE 86
[0978]
(2S)-(1'R,3'S)3-{4-[3'-(Biphenyl-4-yloxy)-1'-cyclopentyloxy]-phenyl-
}-2-methoxy-propionic acid 163
[0979] Step A
[0980] (1S*,3S*)-3-(Biphenyl-4-yloxy)-cyclopentanol 164
[0981] The title compound was prepared starting from
(1R*,3S*)-3-(tert-Butyl-dimethyl-silanyloxy)-cyclopentanol of
Example 82, Step A, and running a Standard Mitsounobu coupling
reaction B (toluene) with 4-phenylphenol. The product then was
deprotected by Standard Procedure E to give the compound after
purification by chromatography.
[0982] Step B
[0983] (1'S,2S,3'S)-3,3,3-Trifluoro-2-methoxy-2-phenyl-propionic
acid 3'-(biphenyl-4-yloxy)-1'-cyclopentyl ester 165
[0984] A mixture of
(1S*,3S*)-3-(Biphenyl-4-yloxy)-cyclopentanol
[0985] From Step A (1 eq) with
(S)-(-)-.alpha.-methoxy-.alpha.-(trifluorom- ethyl)-phenylacetic
acid (1 eq), DMAP (0.1 eq) and EDCI (1.2 eq) in dichloromethane was
stirred at 36.degree. C. over night. The reaction mixture was
cooled and concentrated to dryness. Reconstituted in ether and
washed with HCl 1N, and NaHCO.sub.3. Dry over MsSO4 and
concentrated in vacuo to give a crude that was purify by silica gel
chromatography to give a diastereomeric mixture which was separated
using chiral HPLC.
[0986] Step C
[0987] (1S,3S)-3-(Biphenyl-4-yloxy)-cyclopentanol 166
[0988] To a solution of compound from Step C in ethanol an excess
of NaOH 1N was added and the mixture reaction was stirred at room
temperature. The solution was concentrated in vacuo and diluted
with brine. Extracted with ether and concentrated to yield the
title compound.
[0989] Step D
[0990]
(2S)-(1'R,3*S)-3-{4-[3'-(Biphenyl-4-yloxy)-1'-cyclopentyloxy]-pheny-
l}-2-methoxy-propionic acid
[0991] The title compound was prepared using the Standard Procedure
for Mitsounobu coupling-hydrolysis A in Toluene to give the final
compound. MS (ES) for C.sub.27H.sub.28O.sub.5 [M+NH.sub.4].sup.+:
450.2, [M+Na].sup.+: 455.2. .sup.1H-NMR (CDCl.sub.3, 200.15 MHz):
7.56-7.28 (m, 6H), 7.15-7.08 (m, 3H), 6.95 (d, 2H, J=8.9),
6.84-6.73 (m, 2H), 4.81-4.79 (m, 2H), 3.98 (dd, 1H, J=7.0, 4.3),
3.40 (s, 3H), 3.10 (dd, 1H, J=14.2, 4.0), 2.95 (dd, 1H, J=14.2,
7.3), 2.58-2.44 (m, 1H), 2.19-2.02 (m, 5H).
EXAMPLE 87
[0992]
(2S)-(1'S,3'R)3-{4-[3'-[3'-(Biphenyl-4-yloxy)-1'-cyclopentyloxy]-ph-
enyl}-2-methoxy-propionic acid 167
[0993] Step A
[0994] (1'R,2S,3'R)-3,3,3-Trifluoro-2-methoxy-2-phenyl-propionic
acid 3'-(biphenyl-4-yloxy)-1'-cyclopentyl ester 168
[0995] A mixture of (1S*,3S*)-3-(Biphenyl-4-yloxy)-cyclopentanol
from Step A (1 eq) with
(S)-(-)-.alpha.-methoxy-.alpha.-(trifluoromethyl)-phenylace- tic
acid (1 eq), DMAP (0.1 eq) and EDCI (1.2 eq) in dichloromethane was
stirred at 36.degree. C. over night. The reaction mixture was
cooled and concentrated to dryness. Reconstituted in ether and
washed with HCl 1N, and NaHCO.sub.3. Dry over MsSO4 and
concentrated in vacuo to give a crude that was purify by silica gel
chromatography to give a diastereomeric mixture which was separated
using chiral HPLC.
[0996] Step B
[0997]
(2S)-(1'S,3'R)3-{4-[3'-(Biphenyl-4-yloxy)-1'-cyclopentyloxy]-phenyl-
}-2-methoxy-propionic acid
[0998] The title compound was prepared using the same procedures as
in Example 86, Steps C and D, to give the final compound. MS (ES)
for C.sub.27H.sub.28O.sub.5 [M+NH.sub.4].sup.+: 450.2,
[M+Na].sup.+: 455.2. .sup.1H-NMR (CDCl.sub.3, 200.15 MHz):
7.56-7.28 (m, 6H), 7.15-7.08 (m, 3H), 6.95 (d, 2H, J=8.9),
6.84-6.73 (m, 2H), 4.81-4.79 (m, 2H), 3.98 (dd, 1H, J=7.0, 4.3),
3.40 (s, 3H), 3.10 (dd, 1H, J=14.2, 4.0), 2.95 (dd, 1H, J=14.2,
7.3), 2.58-2.44 (m, 1H), 2.19-2.02 (m, 5H).
EXAMPLE 88
[0999]
(2S)-(1'S,3'S)3-{4-[3'-(Biphenyl-4-yloxy)-1'-cyclopentyloxy]-phenyl-
}-2-methoxy-propionic acid 169
[1000] The title compound was prepared from
(2S)-(1'R*,2'R*)-3-{4-[3-(Biph-
enyl-4-yloxy)-cyclopentyloxy]-phenyl}-2-methoxy-propionic acid from
0, Step D, which was purified by chiral-HPLC to give the
corresponding enantiomer. MS (ES) for C.sub.27H.sub.28O.sub.5
[M+NH.sub.4].sup.+: 450.2, [M+Na].sup.+: 455.2. .sup.1H-NMR
(CDCl.sub.3, 200.15 MHz): .delta. 7.57-7.29 (m, 7H), 7.15 (d, 2H,
J=8.6), 6.94 (d, 2H, J=8.9), 6.81 (d, 2H, J=8.6), 4.99-4.91 (m,
2H), 3.99 (dd, 1H, J=7.3, 4.6), 3.41 (s, 3H), 3.10 (dd, 1H, J=14.2,
4.6), 2.96 (dd, 1H, J=14.5, 7.3), 2.31 (t, 2H, J=4.8), 2.26-1.97
(m, 4H).
EXAMPLE 89
[1001]
(2S)-(1'R,3'R)-3-{4-[3'-(Biphenyl-4-yloxy)-1'-cyclopentyloxy]-pheny-
l}-2-methoxy-propionic acid 170
[1002] The title compound was prepared from
(2S)-(1'R*,2'R*)3-{4-[3-(Biphe-
nyl-4-yloxy)cyclopentyloxy]-phenyl}-2-methoxy-propionic acid from
Example 81, Step D, which was purified by chiral-HPLC to give the
corresponding enantiomer. .sup.1H-NMR (CDCl.sub.3, 200.15 MHz): d
7.57-7.29 (m, 7H), 7.15 (d, 2H, J=8.6), 6.94 (d, 2H, J=8.9), 6.81
(d, 2H, J=8.6), 4.99-4.91 (m, 2H), 3.99 (dd, 1H, J=7.3, 4.6), 3.41
(s, 3H), 3.10 (dd, 1H, J=14.2, 4.6), 2.96 (dd, 1H, J=14.5, 7.3),
2.31 (t, 2H, J=4.8), 2.26-1.97 (m, 4H). MS (ES) for
C.sub.27H.sub.28O.sub.5 [M+Na].sup.+: 455.
EXAMPLE 90
[1003]
(2S)-(1'R,3'S)-3-{4-[3'-(Biphenyl-4-yloxy)-1'-cyclohexyloxy]-phenyl-
}-2-methoxy-propionic acid 171
[1004] Step A
[1005] 3-(tert-Butyl-dimethyl-silanyloxy)-cyclohexanol 172
[1006] The title compound was prepared following the Standar
Procedure D for the monoprotection of diols, to give the product as
a colorless oil.
[1007] Step B
[1008]
[3-(Biphenyl-4-yloxy)-cyclohexyloxy]-tert-butyl-dimethyl-silane
173
[1009] The title compound was prepared using the Standard Procedure
for Mitsounobu coupling B (Toluene) to give the product as a
colorless oil. MS (ES) for C.sub.24H.sub.34O.sub.2Si: [M+H].sup.+:
383.3.
[1010] Step C
[1011] 3-(Biphenyl-4-yloxy)-cyclohexanol 174
[1012] The title compound was prepared by the Standard Procedure E
for cleveage the protected alcohols to give a mixture of the four
isomers of the compounds. The mixture was purified by silicagel
chromatography to give the corresponding two isomers (trans).
(1S*,3S*)-3-(Biphenyl-4-yloxy- )-cyclohexanol .sup.1H-NMR (CDCl3,
500.00 MHz): 7.55 (d, J=7.3 Hz, 2H); 7.51 (d, J=8.5 Hz, 2H); 7.41
(t, J=7.9 Hz, 2H); 7.30 (t, J=7.3 Hz, 1H); 6.97 (d, J=8.5 Hz, 2H);
4.74-4.72 (m, 1H); 4.20-4.15 (m, 1H); 2.09-2.04 (m, 1H); 1.86-1.70
(m, 6H); 1.53-1.27 (m, 3H)ppm and
(cis)(1R*,3S)-3-(Biphenyl-4-yloxy)-cyclohexanol .sup.1H-NMR
(CDCl.sub.3, 500.00 MHz): 7.54 (d, J=7.6 Hz, 2H); 7.51 (d, J=8.5
Hz, 2H); 7.41 (t, J=7.6 Hz, 2H); 7.30 (t, J=7.3 Hz, 1H); 6.97 (d,
J=8.5 Hz, 2H); 4.39-4.36 (m, 1H); 3.83-3.80 (m, 1H); 2.31 (d,
J=12.3 Hz, 1H); 2.04-1.85 (m, 4H); 1.72-1.34 (m, 10H)ppm.
[1013] Step D
[1014] (1R,3S)-(2S)-3,3,3-Trifluoro-2-methoxy-2-phenyl-propionic
acid 3-(biphenyl-4-yloxy)-1-cyclohexyl ester 175
[1015] A mixture of (1R*,3S*)-3-(Biphenyl-4-yloxy)-cyclohexanol
from Step C (1 eq) with
(S)-(-)-.alpha.-methoxy-.alpha.-(trifluoromethyl)-phenylace- tic
acid (1 eq), DMAP (0.1 eq) and EDCI (1.2 eq) in dichloromethane was
stirred at 36.degree. C. over night. The reaction mixture was
cooled and concentrated to dryness. Reconstituted in: ether and
washed with HCl 1N, and NaHCO.sub.3. Dry over MsSO.sub.4 and
concentrated in vacuo to give a crude that was purified by silica
gel chromatography to give a diastereomeric mixture which was
separated using chiral HPLC
[1016] Step E
[1017] (1R,3S)-3-(Biphenyl-4-yloxy)-cyclohexanol 176
[1018] To a solution of compound from Step D in ethanol an excess
of NaOH 1N was added and the mixture reaction was stirred at room
temperature. The solution was concentrated in vacuo and diluted
with brine. Extracted with ether and concentrated to yield the
title compound.
[1019] Step F
[1020]
(2S)-(1'S,3'R)-3-{4-[3'-(Biphenyl-4-yloxy)-1'-cyclohexyloxy]-phenyl-
}-2-methoxy-propionic acid
[1021] The title compound was prepared using the Standard Procedure
for Mitsounobu coupling-hydrolysis A in Toluene to give the final
compound. .sup.1H-NMR (CDCl.sub.3, 200.15 MHz): 7.73-7.28 (m, 7H),
7.12 (dd, 2H, J=10.2, 8.6), 7.00-6.93 (m, 1H), 6.86-6.73 (m, 2H),
4.34-4.19 (m, 2H), 3.98 (dd, 1H, J=7.3, 4.3), 3.39 (s, 3H), 3.09
(dd, 1H, J=14.2, 4.0), 2.94 (dd, 1H, J=14.5, 7.3), 2.67-2.61 (m,
1H), 2.27-2.18 (m, 1H), 1.96-1.93 (m, 1H), 1.71-1.54 (m, 1H),
1.46-1.37 (m, 3H).
EXAMPLE 91
[1022]
(2S)-(1'S,3'R)-3-{4-[3'-(Biphenyl-4-yloxy)-1'-cyclohexyloxy]-phenyl-
}-2-methoxy-propionic acid 177
[1023] Step A
[1024] (1S,3R)-(2S)-3,3,3-Trifluoro-2-methoxy-2-phenyl-propionic
acid 3-(biphenyl-4-yloxy)-1-cyclohexyl ester 178
[1025] A mixture of (1R*,3S*)-3-(Biphenyl-4-yloxy)-cyclohexanol
from Example 90, Step C (1 eq) with
(S)-(-)-.alpha.-methoxy-.alpha.-(trifluoro- methyl)-phenylacetic
acid (1 eq), DMAP (0.1 eq) and EDCI (1.2 eq) in dichloromethane was
stirred at 36.degree. C. over night. The reaction mixture was
cooled and concentrated to dryness. Reconstituted in ether and
washed with HCl 1N, and NaHCO.sub.3. Dry over MsSO.sub.4 and
concentrated in vacuo to give a crude that was purified by silica
gel chromatography to give a diastereomeric mixture which was
separated using chiral HPLC.
[1026] Step B
[1027] (1S,3R)-3-(Biphenyl-4-yloxy)-cyclohexanol 179
[1028] The compound was prepared using the same procedure as in
Example 90, Step E.
[1029] Step C
[1030]
(2S)-(1'S,3'R)-3-{4-[3'-(Biphenyl-4-yloxy)-1'-cyclohexyloxy]-phenyl-
}-2-methoxy-propionic acid
[1031] The title compound was prepared using the Standard Procedure
for Mitsounobu coupling-hydrolysis A in toluene to give the final
compound. .sup.1H-NMR (CDCl.sub.3, 200.15 MHz): 7.73-7.28 (m, 7H),
7.12 (dd, 2H, J=10.2, 8.6), 7.00-6.93 (m, 1H), 6.86-6.73 (m, 2H),
4.34-4.19 (m, 2H), 3.98 (dd, 1H, J=7.3, 4.3), 3.39 (s, 3H), 3.09
(dd, 1H, J=14.2, 4.0), 2.94 (dd, 1H, J=14.5, 7.3), 2.67-2.61 (m,
1H), 2.27-2.18 (m, 1H), 1.96-1.93 (m, 1H), 1.71-1.54 (m, 1H),
1.46-1.37 (m, 3H).
EXAMPLE 92
[1032]
(2S)-(1'R,3'R)-3-{4-[3'-(Biphenyl-4-yloxy)-1'-cyclohexyloxy]-phenyl-
}-2-methoxy-propionic acid 180
[1033] Step A
[1034] (1R,3S)-(2S)-3,3,3-Trifluoro-2-methoxy-2-phenyl-propionic
acid 3-(biphenyl-4-yloxy)-1-cyclohexyl ester 181
[1035] A mixture of (1R*,3R*)-3-(Biphenyl-4-yloxy)-cyclohexanol
(trans), from Example 90, Step C (1 eq) with
(S)-(-)-.alpha.-methoxy-.alpha.-(trif- luoromethyl)-phenylacetic
acid (1 eq), DMAP (0.1 eq) and EDCI (1.2 eq) in dichloromethane was
stirred at 36.degree. C. over night. The reaction mixture was
cooled and concentrated to dryness. Reconstituted in ether and
washed with HCl 1N, and NaHCO.sub.3. Dry over MsSO4 and
concentrated in vacuo to give a crude that was purify by silcagel
chromatography to give a diastereomeric mixture which was separated
using chiral HPLC.
[1036] Step B
[1037] (1R,3R)-3-(Biphenyl-4-yloxy)-cyclohexanol 182
[1038] The compound was prepared using the same procedure as in
Example 90, Step E.
[1039] Step C
[1040]
(2S)-(1'R,3'R)-3-{4-[3'-(Biphenyl-4-yloxy)-1'-cyclohexyloxy]-phenyl-
}-2-methoxy-propionic acid
[1041] The title compound was prepared using the Standard Procedure
for Mitsounobu coupling-hydrolysis A in toluene to give the final
compound. .sup.1H-NMR (CDCl.sub.3, 200.15 MHz): 7.57-7.27 (m, 7H),
7.13 (d, 2H, J=8.6), 6.96 (dd, 2H, J=6.7, 2.1), 6.83 (d, 2H,
J=8.9), 4.75-4.72 (m, 2H), 4.00-3.95 (m, 1H), 3.38 (s, 3H), 3.09
(dd, 1H, J=14.8, 4.3), 2.94 (dd, 1H, J=14.5, 7.5), 2.12-2.05 (m,
3H), 1.80-1.78 (m, 5H).
EXAMPLE 93
[1042]
(2S)-(1'S,3'S)-3-{4-[3'-(Biphenyl-4-yloxy)-1'-cyclohexyloxy]-phenyl-
}-2-methoxy-propionic acid 183
[1043] Step A
[1044] (1S,3S)-(2S)-3,3,3-Trifluoro-2-methoxy-2-phenyl-propionic
acid 3-(biphenyl-4-yloxy)-1-cyclohexyl ester 184
[1045] A mixture of (1R*,3R*)-3-(Biphenyl-4-yloxy)-cyclohexanol
(trans), from Example 90, Step C (1 eq) with
(S)-(-)-.alpha.-methoxy-.alpha.-(trif- luoromethyl)-phenylacetic
acid (1 eq), DMAP (0.1 eq) and EDCI (1.2 eq) in dichloromethane was
stirred at 36.degree. C. over night. The reaction mixture was
cooled and concentrated to dryness. Reconstituted in ether and
washed with HCl 1N, and NaHCO.sub.3. Dry over NaSO4 and
concentrated in vacuo to give a crude that was purify by silica gel
chromatography to give a diastereomeric mixture which was separated
using chiral HPLC.
[1046] Step B
[1047] (1S,3S)-3-(Biphenyl-4-yloxy)-cyclohexanol 185
[1048] The compound was prepared using the same procedure as in
Example 90, Step E.
[1049] Step C
[1050]
(2S)-(1'S,3'S)-3-{4-[3'-(Biphenyl-4-yloxy)-1'-cyclohexyloxy]-phenyl-
}-2-methoxy-propionic acid
[1051] The title compound was prepared using the Standard Procedure
for Mitsounobu coupling-hydrolysis A in toluene to give the final
compound. .sup.1H-NMR (CDCl.sub.3, 200.15 MHz): 7.57-7.27 (m, 7H),
7.13 (d, 2H, J=8.6), 6.96 (dd, 2H, J=6.7, 2.1), 6.83 (d, 2H,
J=8.9), 4.75-4.72 (m, 2H), 4.00-3.95 (m, 1H), 3.38 (s, 3H), 3.09
(dd, 1H, J=14.8, 4.3), 2.94 (dd, 1H, J=14.5, 7.5), 2.12-2.05 (m,
3H), 1.80-1.78 (m, 5H).
EXAMPLE 94
[1052]
(2S)-3-{1-[3-(4-Benzoyl-phenoxy)-propoxy]-phenyl}-2-methoxy-propion-
ic acid 186
[1053] Step A
[1054]
(2S)-3-[4-(tert-Butyl-dimethyl-silanyloxy)-phenyl]-2-methoxy-propio-
nic acid 187
[1055] To a solution of (2S)-3-hydroxyphenyl-2-methoxy-propionic
acid (7.30 g; 37.2 mmol) in 40 mL of dry DMF was added
tert-butyldimethylsilyl chloride (11.80 g, 78.2 mmol) and imidazole
(5.32 g, 78.2 mmol). The solution was stirred at room temperature
overnight. Water (40 mL) was added, and the aqueous phase was
extracted with hexanes (40 mL). The organic layer was washed with
water (50 mL), dried (MgSO.sub.4), and concentrated. The crude
material was dissolved in THF (20 mL), and saturated NaHCO.sub.3
solution (20 mL) was added. The resulting mixture was stirred for 2
hours at room temperature. The aqueous layer was extracted with
ethyl acetate (40 mL), acidified to pH 3, and extracted again with
ethyl acetate (3.times.40 mL). The combined organic layers were
washed with brine (60 mL) and dried (MgSO.sub.4), and concentrated
to a yellow oil (11.5 g, 99%). .sup.1H-NMR (200.15 MHz,
CDCl.sub.3): .delta. 7.09 (d, 2H, J=8.3), 6.76 (d, 2H, J=8.6), 3.97
(dd, 1H, J=7.5, 4.3), 3.38 (s, 3H), 3.09 (dd, 1H, J=14.5, 4.3),
2.93 (dd, 1H, J=14.2, 7.3), 0.97 (s, 9H), 0.1.8 (6H, s).
[1056] Step B
[1057] Preparation of
(2S)-3-[4-(tert-Butyl-dimethyl-silanyloxy)-phenyl]-2-
-methoxy-propionic acid linked to Wang's Resin 188
[1058] The reaction was carried out in a polypropylene syringe
equipped with a polypropylene frit. Wang's resin (1 eq, ca. 1.2
mmol/g resin) was suspended in dichloromethane (0.05 M) and
(2S)-3-[4-(tert-butyldimethylsi-
lanyloxy)phenyl]-2-methoxypropionic acid (1.5 eq),
disopropylcarbodiimide (2.0 eq), and a catalytic amount of
dimethylaminopyridine were added. The mixture was shaken at room
temperature overnight. The reaction solvent was removed, and the
resin was washed sequentially with CH.sub.2Cl.sub.2 (2.times.), DMF
(2.times.), CH.sub.2Cl.sub.2 (2.times.), methanol, and
CH.sub.2Cl.sub.2 (2.times.). The resin was dried under vacuum for 5
hours. The resin was suspended in CH.sub.2Cl.sub.2 (0.05 M) and
treated with acetic anhydride (5 eq) and a catalytic amount of
dimethyaminopyridine for 2 hours. The solvent was removed and the
resin washed sequentially with a mixture of 1:1 acetic
acid/CH.sub.2Cl.sub.2 (3.times.), CH.sub.2Cl.sub.2 (2.times.),
methanol, CH.sub.2Cl.sub.2 (2.times.) and dried under vacuum
overnight to give
(2S)-3-[4-(tert-butyldimethylsilanyloxy)-phenyl]-2-methoxy-propionic
acid linked to Wang's Resin.
[1059] Step C
[1060] Preparation of (2S)-3-(4-Hydroxy-phenyl)-2-methoxy-propionic
acid linked to Wang's Resin 189
[1061] The reaction was carried out in a polypropylene syringe
equipped with a polypropylene frit. To a suspension of
(2S)-3-[4-(tert-butyldimeth-
ylsilanyloxy)-phenyl]-2-methoxy-propionic acid linked to Wang's
Resin (1 eq) in dichloromethane (0.05 M) was added
tetrabutylammonium fluoride (ca 5 eq). The mixture was shaken at
room temperature for 3 hours. The solvent was removed, and the
resin was washed sequentially with CH.sub.2C.sub.2 (2.times.), DMF
(2.times.), CH.sub.2Cl.sub.2 (2.times.), is methanol, and
CH.sub.2Cl.sub.2 (2.times.). The resin was dried under vacuum
overnight to produce (2S)-3-(4-hydroxy-phenyl)-2-methoxy-propionic
acid linked to Wang's Resin. Cleavage of 20 mg of the resin in
TFA/CH.sub.2Cl.sub.2 1:1 followed by evaporation of the solvent
produced (S)-3-(4-hydroxy-phenyl)-2-methoxy-propionic acid as an
oil. .sup.1H-NMR (200.15 MHz, CDCl.sub.3): .delta. 7.10 (d, 2H,
J=8.6), 6.76 (d, 2H, J=8.6), 3.99 (dd, 1H, J=7.0, 4.6), 3.41 (s,
3H), 3.10 (dd, 1H, J=14.5, 4.6), 2.95 (dd, 1H, J=14.5, 7.5).
[1062] Step D
[1063] Preparation of (2S)-3-[4-(3-Hydroxy-propoxy
phenyl]-2-methoxy-propi- onic acid linked to Wang's Resin 190
[1064] The title compound was prepared from
(2S)-3-(4-hydroxy-phenyl)-2-me- thoxy-propionic acid linked to
Wang's Resin via Mitsunobu coupling (Standard Procedure F) to
produce (2S)-3-[4-(3-hydroxy-propoxy)-phenyl]-2- -methoxy-propionic
acid linked to Wang's Resin. Cleavage of 20 mg of the resin in
TFA/CH.sub.2Cl.sub.2 1:1 followed by evaporation of the solvent
produced (2S)-3-[4-(3-hydroxy-propoxy)-phenyl]-2-methoxy-propionic
acid as an oil. .sup.1H-NMR (200.15 MHz, CDCl.sub.3): .delta. 7.16
(d, 2H, J=8.6), 6.82 (d, 2H, J=8.6), 4.56 (t, 1H, J=6.2), 4.09 (2H,
dd, J=13.2, 5.9), 3.99 (dd, 1H, J=6.7, 4.0), 3.90 (1H, t, J=5.9),
3.40 (s, 3H), 3.10 (dd, 1H, J=14.2, 4.0), 2.96 (dd, 1H, J=14.2,
7.3), 2.22 (qn, 1H, J=5.9), 2.05 (qn, 1H, J=5.9).
[1065] Step E
[1066]
(2S)-3-{4-[3-(4-Benzoyl-phenoxy)-propoxy]-phenyl}-2-methoxy-propion-
ic acid
[1067] The title compound was prepared from
(2S)-3-[4-(3-hydroxy-propoxy)-- phenyl]-2-methoxy-propionic acid
linked to Wang's Resin via the Mitsunobu coupling-cleavage from the
resin procedure (Standard Procedure G) to give 1.6 mg of a white
solid (6%). .sup.1H-NMR (200.15 MHz, CDCl.sub.3): .delta. 7.82-7.72
(m, 4H), 7.57-7.43 (m, 3H), 7.14 (d, 2H, J=8.8), 6.96 (d, 2H,
J=8.8), 6.84 (d, 2H, J=8.8), 4.25 (t, 2H, J=6.0), 4.14 (t, 2H,
J=6.0), 4.00 (dd, 1H, J=6.8, 4.6 Hz), 3.41 (s, 3H), 3.10 (dd, 1H,
J=14.1, 4.6), 2.97 (dd, 1H, J=14.1, 6.8), 2.28 (qn, 2H, J=6.0).
EXAMPLE 95
[1068]
(2S)-3-(4-{3-[4-(4-Fluoro-benzoyl)-phenoxy]-propoxy}-phenyl)-2-meth-
oxy-propionic acid 191
[1069] The title compound was prepared from
(2S)-3-[4-(3-hydroxy-propoxy)-- phenyl]-2-methoxy-propionic acid
linked to Wang's Resin (Example 94, Step D) via Mitsunobu coupling
with 4-hydroxybenzophenone and cleavage from the resin (Standard
Procedure G) gave an oil (7%). .sup.1H-NMR (200.15 MHz,
CDCl.sub.3): .delta. 7.82-7.73 (m, 4H), 7.19-7.10 (m, 4H), 6:96 (d,
2H, J=8.9), 6.84 (d, 2H, J=8.9), 4.25 (t, 2H, J=6.0), 4.15 (t, 2H,
J=6.0), 4.00 (dd, 1H, J=6.7, 4.6), 3.41 (s, 3H), 3.10 (dd, 1H,
J=14.1, 4.6), 2.97 (dd, dd, J=14.1, 6.8), 2.28 (qn, 2H, J=6.0). MS
(ES) for C.sub.26H.sub.25FO.sub.6 [M+H].sup.+: 453.2, [M+Na].sup.+:
475.2.
EXAMPLE 96
[1070]
(2S)-3-{4-[3-(4-Benzoyl-phenoxy)-propoxy]-phenyl}-2-methoxy-propion-
ic acid 192
[1071] The title compound was prepared from
(2S)-3-[4-(3-hydroxy-propoxy)-- phenyl]-2-methoxy-propionic acid
linked to Wang's Resin (Example 94, Step D) via Mitsunobu coupling
with 4-hydroxydiphenylmethane and cleavage from the resin (Standard
Procedure G) produced a white solid (5%). .sup.1H-NMR (200.15 MHz,
CDCl.sub.3): .delta. 7.29-7.13 (m, 6H), 7.08 (d, 2H, J=8.9), 6.82
(d, 2H, J=8.6), 4.12 (t, 4H, J=6.2), 3.97 (dd, 1H, J=6.6, 4.0),
3.39 (s, 3H), 3.10 (dd, 1H, J=14.2, 4.0), 2.95 (dd, 1H, J=14.2,
6.6), 2.22 (qn, 2H, J=6.2).
EXAMPLE 97
[1072]
(2S)-2-Methoxy-3-{4-[3-(3-phenylamino-phenoxy)-propoxy]-phenyl}-pro-
pionic acid 193
[1073] The title compound was prepared from
(2S)-3-[4-(3-hydroxy-propoxy)-- phenyl]-2-methoxy-propionic acid
linked to Wang's Resin (Example 94, Step D) via Mitsunobu coupling
with 3-hydroxydiphenylamine and cleavage from the resin (Standard
Procedure G) gave an oily solid (4%). .sup.1H-NMR (200.15 MHz,
CDCl.sub.3): .delta. 7.31-6.81 (m, 8H), 6.83 (d, 2H, J=8.6),
6.65-6.62 (m, 2H), 6.48 (dd, 1H, J=8.2, 2.1), 4.12 (t, 4H, J=6.2),
3.99 (dd, 1H, J=7.0, 4.4), 3.40 (s, 3H), 3.10 (dd, 1H, J=14.2,
4.4), 2.95 (dd, 1H, J=14.2, 7.0), 2.22 (qn, 2H, J=6.2).
EXAMPLE 98
[1074]
(2S)-3-{4-[3-(4-Butyl-phenoxy)-propoxy]-phenyl}-2-methoxy-propionic
acid 194
[1075] The title compound was prepared from
(2S)-3-[4-(3-hydroxy-propoxy)-- phenyl]-2-methoxy-propionic acid
linked to Wang's Resin (Example 94, Step D) via Mitsunobu coupling
with 4'-butylphenol and cleavage from the resin (Standard Procedure
G) gave an oily solid (7%). .sup.1H-NMR (200.15 MHz, CDCl.sub.3):
.delta. 7.11 (dd, 4H, J=12.7, 8.6), 6.82 (dd, 4H, J=8.6, 3.2), 4.12
(t, 4H, J=6.2), 3.97 (dd, 1H, J=7.7, 4.4), 3.38 (s, 3H), 3.30 (dd,
1H, J=14.5, 4.4), 2.94 (dd, 1H, J=14.5, 7.7), 2.54 (t, 2H, J=7.7),
2.23 (qn, 2H, J=6.2), 1.63-1.48 (m, 2H), 1.42-1.24 (m, 2H), 0.91
(t, 3H, J=7.2).
EXAMPLE 99
[1076]
(2S)-3-(4-{3-[4-(2-Fluoro-benzoyl)-phenoxy]-propoxy}-phenyl)-2-meth-
oxy-propionic acid 195
[1077] The title compound was prepared from
(2S)-3-[4-(3-Hydroxy-propoxy)-- phenyl]-2-methoxy-propionic acid
linked to Wang's Resin (Example 94, Step D) via Mitsunobu coupling
with 2-fluoro-4'-hydroxybenzophenone and cleavage from the resin
(Standard Procedure G) gave an oily solid (7%). .sup.1H-NMR (200.15
MHz, CDCl.sub.3): .delta. 7.81 (dd, 2H, J=8.8, 1.3), 7.54-7.45 (m,
2H), 7.28-7.09 (m, 4H), 6.94 (d, 2H, J=8.6), 6.83 (d, 2H, J=8.6),
4.24 (t, 2H, J=6.2), 4.14 (t, 2H, J=6.2), 3.98 (dd, 1H, J=7.0,
4.6), 3.40 (s, 3H), 3.09 (dd, 1H, J=14.2, 4.6), 2.96 (dd, 1H,
J=14.2, 7.0), 2.28 (q, 2H, J=6.2).
EXAMPLE 100
[1078]
(2S)-2-Methoxy-3-{4-[3-(9-oxo-9H-fluoren-2-yloxy-propoxy]-phenyl}-p-
ropionic acid 196
[1079] The title compound was prepared from
(2S)-3-[4-(3-Hydroxy-propoxy)-- phenyl]-2-methoxy-propionic acid
linked to Wang's Resin (Example 94, Step D) via Mitsunobu coupling
with 2-hydroxy-9-fluorenone and cleavage from the resin (Standard
Procedure G) gave an oily solid. .sup.1H-NMR (200.15 MHz,
CDCl.sub.3): 7.59 (d, 1H, J=7.0); 7.43-7.37 (m, 3H); 7.26-7.13 (m,
4H); 6.98 (dd, 1H, J=8.1, 2.4); 6.85 (d, 2H, J=8.6); 4.17 (qui, 4H,
J=5.6); 3.99 (dd, 1H, J=7.0, 4.6); 3.40 (s, 3H); 3.10 (dd, 1H,
J=14.2, 4.6); 2.96 (dd, 1H, J=14.2, 7.0); 2.32-2.23 (m, 4H)
ppm.
EXAMPLE 101
[1080]
(2S)-2-Methoxy-3-{4-[3-(2-methyl-benzothiazol-5-yloxy)-propoxy]-phe-
nyl}-propionic acid 197
[1081] The title compound was prepared from
(2S)-3-[4-(3-Hydroxy-propoxy)-- phenyl]-2-methoxy-propionic acid
linked to Wang's Resin (Example 94, Step D) via Mitsunobu coupling
with 2-methyl-5-benzothiazolol and cleavage from the resin
(Standard Procedure G) to give an oily solid. .sup.1H-NMR (200.15
MHz, CDCl.sub.3): 7.65 (d, 1H, J=8.9), 7.36-7.35 (m, 1H), 7.16 (d,
2H, J=8.9), 7.03 (dd, 1H, J=8.9, 2.4), 6.86 (dd, 2H, J=6.5, 1.9),
4.22 (t, 2H, J=35.9), 4.18 (t, 2H, J=6.2), 4.01 (dd, 2H, J=6.4,
5.4), 3.43 (s, 3 I), 3.14-2.94 (m, 2H), 2.87 (s, 3H), 2.27 (qn, 2H,
J=6.2) ppm.
EXAMPLE 102
[1082]
(2S)-2-Methoxy-3-{4-[3-(3-morpholin-4-yl-phenoxy)-propoxy]-phenyl}--
propionic acid 198
[1083] The title compound was prepared from
(2S)-3-[4-(3-Hydroxy-propoxy)-- phenyl]-2-methoxy-propionic acid
linked to Wang's Resin (Example 94, Step D) via Mitsunobu coupling
with 3-(4-morpholino)phenol and cleavage from the resin (Standard
Procedure G) gave an oily solid. .sup.1H-NMR (200.15 MHz,
CDCl.sub.3): 7.32-7.23 (m, 1H), 7.14-7.10 (m, 2H), 6.84-6.69 (m,
5H), 4.14 (q, 4H, J=5.6), 4.02-3.94 (m, 5H), 3.40 (s, 3H),
3.33-3.28 (m, 4H), 3.13-2.91 (m, 2H), 2.23 (qn, 2H, J=5.9) ppm.
EXAMPLE 103
[1084]
(2S)-3-{4-[3-(Biphenyl-2-yloxy)-propoxy]-phenoxy}-2-methoxy-propion-
ic acid 199
[1085] The title compound was prepared from
(2S)-3-[4-(3-Hydroxy-propoxy)-- phenyl]-2-methoxy-propionic acid
linked to Wang's Resin (Example 94, Step D) via Mitsunobu coupling
with 2-phenylphenol and cleavage from the resin (Stand Procedure G)
to give the title compound. .sup.1H-NMR (200.15 MHz, CDCl.sub.3):
7.51-7.43 (m, 2H), 7.38-7.29 (m, 5H), 7.15-6.98 (m, 4H), 6.79-6.72
(m, 2H), 4.15 (t, 2H, J=5.9 Hz), 4.04-3.96 (m, 3H), 3.39 (s, 3H),
3.15-2.90 (m; 2H), 2.15 (qn, 2H, J=5.9 Hz) ppm.
EXAMPLE 104
[1086]
(2S)-3-{4-[3-(4-Cyclopentyl-phenoxy)-propoxy]-phenyl}-2-methoxy-pro-
pionic acid 200
[1087] The title compound was prepared from
(2S)-3-[4-(3-Hydroxy-propoxy)-- phenyl]-2-methoxy-propionic acid
linked to Wang's Resin (Example 94, Step D) via Mitsunobu coupling
with 4-cyclopentylphenol and cleavage from the resin (Standard
Procedure G) gave an oily solid.
EXAMPLE 105
[1088]
(2S)-3-{4-[3-(4-Cyano-3-fluoro-phenoxy]-phenyl}-2-methoxy-propionic
acid 201
[1089] The title compound was prepared from
(2S)-3-[4-(3-Hydroxy-propoxy)-- phenyl]-2-methoxy-propionic acid
linked to Wang's Resin (Example 94, Step D) via Mitsunobu coupling
with 2-fluoro-4-hydroxybenzonitrile and cleavage from the resin
(Standard Procedure G) gave an oily solid.
EXAMPLE 106
[1090]
(2S)-3-{4-[3-(2,4-Difluoro-phenoxy)-propoxy]-phenyl}-2-methoxy-prop-
ionic acid 202
[1091] The title compound was prepared from
(2S)-3-[4-(3-Hydroxy-propoxy)-- phenyl]-2-methoxy-propionic acid
linked to Wang's Resin (Example 94, Step D) via Mitsunobu coupling
with 2,4-difluorophenol and cleavage from the resin (Standard
Procedure G) gave an oily solid.
EXAMPLE 107
[1092]
(2S)-2-Methoxy-3-{4-[3-(4-trifluoromethyl-phenoxy)-propoxy]-phenyl}-
-propionic acid 203
[1093] The title compound was prepared from
(2S)-3-[4-(3-Hydroxy-propoxy)-- phenyl]-2-methoxy-propionic acid
linked to Wang's Resin (Example 94, Step D) via Mitsunobu coupling
with 4-trifluoromethylphenol and cleavage from the resin (Standard
Procedure G) gave an oily solid.
EXAMPLE 108
[1094]
(2S)-2-Methoxy-3'-{4-[3-(3-trifluoromethyl-phenoxy)-propoxy]-phenyl-
}-propionic acid 204
[1095] The title compound was prepared from
(2S)-3-[4-(3-Hydroxy-propoxy)-- phenyl]-2-methoxy-propionic acid
linked to Wang's Resin Example 94, Step D) via Mitsunobu coupling
with 3-trifluoromethylphenol and cleavage from the resin (Standard
Procedure CG) gave an oily solid.
EXAMPLE 109
[1096]
(2S)-2-Methoxy-3-{4-[3-(5-oxo-5,6,7,8-tetrahydro-naphthalen-2-yloxy-
)-propoxy]-phenyl}-propionic acid 205
[1097] The title compound was prepared from
(2S)-3-[4-(3-Hydroxy-propoxy)-- phenyl]-2-methoxy-propionic acid
linked to Wang's Resin (Example 94, Step D) via Mitsunobu coupling
with 6-hydroxy-1,2,3,4-tetrahydronaphtalenone and cleavage from the
resin (Standard Procedure G) gave an oily solid.
EXAMPLE 110
[1098]
(2S)-3-{4-[3-(3,5-Difluoro-phenoxy)-propoxy]-phenyl}-2-methoxy-prop-
ionic acid 206
[1099] The title compound was prepared from
(2S)-3-[(3-Hydroxy-propoxy)-ph- enyl]-2-methoxy-propionic acid
linked to Wang's Resin (Example 94, Step D) via Mitsunobu coupling
with 3,5-difluorophenol and cleavage from the resin (Standard
Procedure G) gave an oily solid.
EXAMPLE 111
[1100]
(2S)-3-{4-[3-(Isoquinolin-5-yloxy)-propoxy]-phenyl}-2-methoxy-propi-
onic acid 207
[1101] The title compound was prepared from
(2S)-3-[4-(3-Hydroxy-propoxy)-- phenyl]-2-methoxy-propionic acid
linked to Wang's Resin (Example 94, Step D) via Mitsunobu coupling
with 5-hydroxyisoquinolyne and cleavage from the resin (Standard
Procedure G) gave an oily solid.
EXAMPLE 112
[1102]
(2S)-2-Methoxy-3-{4-[3-(4-trifluoromethoxy-phenoxy)-propoxy]-phenyl-
}-propionic acid 208
[1103] The title compound was prepared from
(2S)-3-[4-(3-Hydroxy-propoxy)-- phenyl]-2-methoxy-propionic acid
linked to Wang's Resin (Example 94, Step D) via Mitsunobu coupling
with 4-trifluoromethoxyphenol and cleavage from the resin (Standard
Procedure G) gave an oily solid.
EXAMPLE 113
[1104]
(2S)-3-{4-[3-(4-Fluoro-phenoxy)-propoxy]-phenyl}-2-methoxy-propioni-
c acid 209
[1105] The title compound was prepared from
(2S)-3-[4-(3-Hydroxy-propoxy)-- phenyl]-2-methoxy-propionic acid
linked to Wang's Resin (Example 94, Step D) via Mitsunobu coupling
with 4-fluorophenol and cleavage from the resin (Standard Procedure
G) gave an oily solid.
EXAMPLE 114
[1106]
(2S)-2-Methoxy-3-{4-[3-(4-phenylacetyl-phenoxy)-propoxy]-phenyl}-pr-
opionic acid 210
[1107] The title compound was prepared from
(2S)-3-[4-(3-Hydroxy-propoxy)-- phenyl]-2-methoxy-propionic acid
linked to Wang's Resin (Example 94, Step D) via Mitsunobu coupling
with benzyl-4-hydroxyphenylketone and cleavage from the resin
(Standard Procedure G) gave an oily solid.
EXAMPLE 115
[1108]
(2S)-2-Methoxy-3-(4-3-[4-(1-methyl-1-phenyl-ethyl)-phenoxy]-propoxy-
}-phenyl)-propionic acid 211
[1109] The title compound was prepared from
(2S)-3-[4-(3-Hydroxy-propoxy)-- phenyl]-2-methoxy-propionic acid
linked to Wang's Resin (Example 94, Step D) via Mitsunobu coupling
with 4-cumylphenol and cleavage from the resin (Standard Procedure
G) gave an oily solid.
EXAMPLE 116
[1110]
(2S)-2-Methoxy-3-{4-[3-4-oxo-2-phenyl-4H-chromen-7-yloxy)-propoxy]--
phenyl}-propionic acid 212
[1111] The title compound was prepared from
(2S)-3-[4-(3-Hydroxy-propoxy)-- phenyl]-2-methoxy-propionic acid
linked to Wang's Resin (Example 94, Step D) via Mitsunobu coupling
with 7-hydroxyflavone and cleavage from the resin (Standard
Procedure G) gave an oily solid.
EXAMPLE 117
[1112]
4-{3-[4-(2-Carboxy-2-methoxy-ethyl)-phenoxy]-propoxy}-benzoic acid
benzyl ester 213
[1113] The title compound was prepared from
(2S)-3-[4-(3-Hydroxy-propoxy)-- phenyl]-2-methoxy-propionic acid
linked to Wang's Resin (Example 94, Step D) via Mitsunobu coupling
with benzyl 4-hydroxybenzoate and cleavage from the resin (Standard
Procedure G) gave an oily solid.
EXAMPLE 118
[1114]
(2S)-2-Methoxy-3-{4-[3-(4-oxo-2-phenyl-chroman-6-yloxy)-propoxy]-ph-
enyl}-propionic acid 214
[1115] The title compound was prepared from
(2S)-3-[4-(3-Hydroxy-propoxy)-- phenyl]-2-methoxy-propionic acid
linked to Wang's Resin (Example 94, Step D) via Mitsunobu coupling
with 6-hydroxyflavone and cleavage from the resin (Standard
Procedure G) gave an oily solid.
EXAMPLE 119
[1116]
(2S)-2-Methoxy-3-{4-[3-(4-oxo-2-phenyl-chroman-6-yloxy)-propoxy]-ph-
enyl}-propionic acid 215
[1117] The title compound was prepared from
(2S)-3-[4-(3-Hydroxy-propoxy)-- phenyl]-2-methoxy-propionic acid
linked to Wang's Resin (Example 94, Step D) via Mitsunobu coupling
with 6-hydroxyflavanone and cleavage from the resin (Standard
Procedure G) gave an oily solid.
EXAMPLE 120
[1118]
(2S)-2-Methoxy-3-{4-[3-(4-oxo-2-phenyl-chroman-7-yloxy-propoxy]-phe-
nyl}-propionic acid 216
[1119] The title compound was prepared from
(2S)-3-[4-(3-Hydroxy-propoxy)-- phenyl]-2-methoxy-propionic acid
linked to Wang's Resin Example 94, Step D) via Mitsunobu coupling
with 7-hydroxyflavanone and cleavage from the resin (Standard
Procedure G) gave an oily solid.
EXAMPLE 121
[1120]
(2S)-2-Methoxy-3-(4-{3-[4-(4-trifluoromethyl-phenoxy)-phenoxy]-prop-
oxy}-phenyl)-propionic acid 217
[1121] The title compound was prepared from
(2S)-3-[4-(3-Hydroxy-propoxy)-- phenyl]-2-methoxy-propionic acid
linked to Wang's Resin (Example 94, Step D) via Mitsunobu coupling
with 4-(4-trifluoromethyl)phenoxyphenol and cleavage from the resin
(Standard Procedure G) gave an oily solid.
EXAMPLE 122
[1122]
(2S)-3-{4-[2-(4-benzoyl-phenoxy)-ethoxy]-phenyl}-2-methoxy-propioni-
c acid 218
[1123] Step A
[1124] 2-(tert-Butyl-dimethyl-silanyloxy)-ethanol 219
[1125] To a solution of ethylene glycol (1.00 g, 16.1 mmol) in THF
(80 mL) was added NaH (0.65 mg, 16.1 mmol, 60% oil dispersion) at
0.degree. C. The reaction was stirred 1 hour,
tert-butyldimethylsilyl chloride (2.35 g, 16.1 mmol) was added, and
the reaction mixture was allowed to warm to room temperature. After
3 hours at room temperature, Na.sub.2CO.sub.3 saturated solution
(80 mL) was added, and the aqueous layer was extracted with ethyl
acetate (3.times.50 mL). The combined organic layers were washed
with water (80 mL) and brine (80 mL), dried over (MgSO.sub.4), and
concentrated under vacuum. The reaction crude was purified by
silica gel column chromatography (silica gel, hexanes/ethyl
acetate, 2:3) to produce 1.93 g (85%) of a yellow oil. .sup.1H-NMR
(200.15 MHz, CDCl): .delta. 3.74-3.59 (m, 4H), 0.91 (s, 9H), 0.08
(s, 6H).
[1126] Step B
[1127] Preparation of
(2S)-3-{4-[2-(tert-Butyl-dimethyl-silanyloxy)-ethoxy-
]-phenyl}-2-methoxy-propanoic acid linked to Wang's Resin 220
[1128] The title compound was prepared from
(2S)-3-(4-hydroxy-phenyl)-2-me- thoxy-propionic acid linked to
Wang's Resin (Example 94, Step D) via the Mitsunobu coupling
procedure with 2-(tert-butyldimethylsilanyloxy)ethanol (Standard
Procedure B).
[1129] Step C
[1130] Preparation of
(2S)-3-[4-(2-Hydroxyethoxy]-phenyl}-2-methoxy-propan- oic acid
linked to Wang's Resin 221
[1131] The title compound was prepared from
3-{4-[2-tert-butydimethylsilan-
yloxy)ethoxy]-phenyl}-2-methoxy-propanoic acid linked to Wang's
Resin when treated with tetrabutylammonium fluoride in THF as
described in Standard Procedure E. Cleavage of 20 mg of the resin
in TFA/CH.sub.2Cl.sub.2 (1:1) followed by evaporation of the
solvent produced (2S)-3-{4-[2-hydroxy-etho-
xy]-phenyl}-2-methoxy-propanoic acid as an oil. .sup.1H-NMR (200.15
MHz, CDCl.sub.3): .delta. 7.16 (d, 2H, J=8.6), 6.85 (d, 2H, J=8.9),
4.09-3.93 (m, 5H), 3.41 (s, 3H), 3.11 (dd, 1H, J=14.5, 4.0), 2.97
(dd, 1H, J=14.5, 7.2).
[1132] Step D
[1133]
(2S)-3-{4-[2-(4-Benzoyl-phenoxy)-ethoxy]-phenyl}-2-methoxy-propioni-
c acid 222
[1134] The title compound was prepared from
(2S)-3-(4-hydroxy-phenyl)-2-me- thoxy-propionic acid linked to
Wang's Resin via Mitsunobu coupling Standard Procedure G. Cleavage
from the resin gave an oily solid. .sup.1H-NMR (200.15 MHz,
CDCl.sub.3): .delta. 7.84-7.72 (m, 4H), 7.60-7.41 (m, 3H), 7.18 (d,
2H, J=8.6), 6.99 (d, 2H, J=8.9), 6.87 (d, 2H, J=8.7), 4.43-4.32 (m,
4H), 3.96 (dd, 1H, J=7.5, 4.6), 3.65 (s, 3H), 3.09 (dd, 1H, J=14.2,
4.2), 2.95 (dd, 1H, J=14.2, 7.8)ppm.
EXAMPLE 123
[1135]
(2S)-3-{4-[2-(Biphenyl-4-yloxy)-ethoxy]-phenyl}-2-methoxy-propionic
acid 223
[1136] Step A
[1137] (Biphenyl-4-yloxy)-acetic acid ethyl ester 224
[1138] To a solution of 4-phenylphenol (1.02 g, 5.99 mmol) in 10 mL
of DMF at -20.degree. C. was added sodium hydride (1.02 g, 5.99
mmol, 60% oil dispersion) and the mixture stirred at 0.degree. C.
for 30 min. 2-bromoethyl acetate (0.66 mL, 5.99 mmol) was added and
the mixture stirred at room temperature overnight. The solution was
diluted with water (50 mL) and extracted with diethyl ether
(3.times.20 mL). The combined extracts were washed with water
(4.times.20 mL), dried (MgSO.sub.4) and concentrated under vacuum.
0.63 g (41%). .sup.1H-NMR (CDCl.sub.3, 200.15 MHz): 7.57-7.56 (m,
4H), 7.45-7.26 (m, 3H), 6.98 (dd, 2H, J=6.4, 2.1), 4.66 (s, 2H),
4.29 (q, 2H, J=7.3), 1.31 (t, 5H, J=7.3) ppm.
[1139] Step B
[1140] 2-(Biphenyl-4-yloxy)-ethanol 225
[1141] To a solution of (Biphenyl-4-yloxy)-acetic acid ethyl ester
(0.63 g, 2.46 mmol) in dry toluene (15 mL) at -78.degree. C. was
added DIBAL-H 1M in toluene (4.92 mL, 4.92 mmol). The solution was
stirred at -78.degree. C. for 1 hour, warmed to room temperature
and quenched with mixture of a solution of sodium tartrate in water
and ethyl acetate for 1 hour. The layers were separated and the
aqueous phase further extracted with ethyl acetate. The combined
organic layers were dried (MgSO.sub.4), concentrated under vacuum
and the residue purified bu column chromatography (silica gel,
hexanes/Ethyl acetate 4:1, R.sub.f0.1), 48%. .sup.1H-NMR
(CDCl.sub.3, 200.15 MHz): 7.58-7.26 (m, 8H); 7.00 (d, 2H, J=8.6),
4.14 (t, 2H, J=4.6), 4.02-3.98 (m, 2H); 2.04 (t, 1H, J=5.4).
[1142] Step C
[1143]
(2S)-3-{4-[2-(Biphenyl-4-yloxy)-ethoxy]-phenyl}-2-methoxy-propionic
acid
[1144] The title compound was prepared from
2-(Biphenyl-4-yloxy)-ethanol and (2S)-2-Methoxy-3-hydroxyphenyl
propionic acid ethyl ester using the general procedure A (34%).
.sup.1H-NMR (CDCl.sub.3, 200.15 MHz): .delta. 7.55-7.49 (m, 4H);
7.43-7.35 (m, 2H); 7.29 (d, 1H, J=7.3); 7.15 (d, 2H, J=8.8); 7.00
(d, 2H, J=8.8); 6.88 (d, 2H, J=8.8); 4.36-4.29 (m, 4H); 3.98 (dd,
1H, J=7.0, 4.4); 3.39 (s, 3H); 3.10 (dd, 1H, J=14.3, 4.4); 2.95
(dd, 1H, J=14.3, 7.3)ppm. MS (ES) for C.sub.24H.sub.24O.sub.5
[M+NH.sub.4].sup.+: 410.
EXAMPLE 124
[1145]
(2S)-3-{4-[2-(Biphenyl-4-yloxy)-acetyl]-phenyl}-2-methoxy-propionic
acid 226
[1146] Step A
[1147] (2S)-3-(4-Ethynyl-phenyl)-2-methoxy-propionic acid ethyl
ester 227
[1148] To a solution of
(2S)-2-Methoxy-3-(4-trifluoromethanesulfonyloxy-ph- enyl)-propionic
acid ethyl ester (0.100 g, 0.29 mmol) (Example 1, Step A) in 10 mL
of degassed piperidine, was added (trimethylsilyl)acetylene (99,6
mg, 1.015 mmol), tetrakis(triphenylphosphine) Palladium (0) (0.017
g, 0.015 mmol), triphenylphosphine (7.7 mg, 0.029 mmol) and cooper
(I) Iodide (5.5 mg, 0.029 mmol). The solution was stirred for 2
hours at 120.degree. C. and then cooled to room temperature. The
solvent was evaporated under vacuum. The residue was dissolved in
dry THF and 0.4 mL of a solution of tetrabutylamonium fluoride (1.0
M in THF) and 0.02 mL of water were added. The mixture was stirred
at room temperature for 5 min. The solvent was evaporated under
vacuum and the residue partitioned between water (20 ml) and
diethyl ether (20 mL). The layers were separated and the aqueous
solution extracted twice with 20 ml of diethylether. The combined
organic layers were washed with 10% Na.sub.2CO.sub.3 (6.times.20
ml) and brine (20 ml) and dried (MgSO.sub.4). Concentration
produced a yellow oil (38 mg, 56%) .sup.1H-NMR (200.15 MHz,
CDCl.sub.3): .delta. 1.95 (d, 1H, J=7.3), 7.25 (d, 1H, J=7.3), 4.18
(q, 2H, J=7.0), 3.97 (dd, 1H, J=7.3, 5.6), 3.36 (s, 3H), 3.05 (d,
1H, J=5.3), 3.02 (d, 1H, J=2.4 Hz), 1.22 (t, 3H, J=7.25).
[1149] Step B
[1150] (2S) 3-(4-Acetyl-phenyl)-2-methoxy-propionic acid ethyl
ester 228
[1151] To (2S)-3-(4-Ethynyl-phenyl)-2-methoxy-propionic acid ethyl
ester (36 Mg, 0.15 mmol) (Example 29, Step A) were added 4 ml of
formic acid. The solution was stirred for 1 hour at 100.degree. C.
and then cooled to room temperature. The mixture was taken up with
methylene chloride and the solution was washed with water, sodium
carbonate, and water, dried (MgSO.sub.4) and the solvent was
evaporated under vacuum. Obtained a brown liquid (0.035 g, 95%).
.sup.1H-NMR (200.15 MHz, CDCl.sub.3): .delta. 7.43 (d, 1H, J=73),
7.12 (d, 1H, J=7.3), 4.18 (q, 2H, J=7.0), 3.97 (dd, 1H, J=7.3,
5.6), 3.32 (s, 3H), 3.06 (s, 1H), 3.03 (d, 1H, J=2.4 Hz), 2.56 (s,
2H), 1.22 (t, 3H, J=7.25).
[1152] Step C
[1153] (2S) 3-[4-(2-Bromo-acetyl)-phenyl]-2-methoxy-propionic acid
ethyl ester 229
[1154] Powdered cupric bromide (62 mg, 0.28 mmol) was added
portionwise to a solution of
(2S)-3-(4-Acetyl-phenyl)-2-methoxy-propionic acid ethyl ester (35
mg, 0.14 mmol) in CHCl.sub.3 (5 ml) and ethyl acetate (5 mL). The
solution was stirred for 1 hour at 65.degree. C. and then cooled to
room temperature. The mixture was filtered and the solvent
evaporated under vacuum. The residue was purified by chromatography
(silica gel, hexanes/Ethyl Ether 8:2, R.sub.f0.20) to produce a
colorless oil (25 mg, 54%). .sup.1H-NMR (200.15 MHz, CDCl.sub.3):
7.935 (d, 1H, J=7.3), 7.38 (d, 1H, J=7.3), 4.50 (s, 2H), 4.12 (q,
2H, J=7.0), 3.97 (dd, 1H, J=7.3, 5.6), 3.38 (s, 3H), 3.10 (s, 1H),
3.06 (d, 1H, J=2.4 Hz), 1.22 (t, 3H, J=7.25).
[1155] Step D
[1156]
(2S)-3-{4-[2-(Biphenyl-4-yloxy)-acetyl]-phenyl}-2-methoxy-propionic
acid
[1157] The title compound was prepared from a solution of
(2S)-3-[4-(2-Bromo-acetyl)-phenyl]-2-methoxy-propionic acid ethyl
ester (25 mg, 0.076 mmol) in acetonitrile (5 ml). 4-phenylphenol
(29 mg, 0.152 mmol) and K.sub.2CO.sub.3 (31,5 mg, 0.23 mmol) were
added. The solution was stirred for 30 min at 80.degree. C. and
then cooled to room temperature. The mixture was concentrated to
dryness under vacuum and chromatographed in silica gel
(hexanes/Ethyl ether 8:2 to 7:3). Fractions corresponding to the
coupled compound were collected (R.sub.f0.27) and concentrated to
dryness. The mixture thus obtained was dissolved in 4 mL of NaOH 1N
and 12 mL of Methanol and stirred at room temperature until TLC
indicates the disappearance of starting material. The methanol was
eliminated under vacuum and the aqueous solution diluted with 20 mL
of brine and washed with diethyl ether (3.times.15 mL). The aqueous
phase was acidulated with HCl 1N (until pH 3); extracted with ethyl
acetate (3.times.15 mL) and the organic layer dried (MgSO.sub.4)
and concentrated under vacuum. Obtained a colorless oil (9.6 mg,
32%). .sup.1H-NMR (200.15 MHz; CDCl.sub.3): .delta. 7.96 (d, 2H,
J=8.4), 7.55-7.23 (m, 9H), 6.99 (d, 2H, J=8.8), 5.26 (s, 2H), 4.03
(dd, 11, 7.3, 5.6), 3.39 (s, 3H), 3.22 (dd, 1H, J=14.3, 5.5), 3.03
(dd, 1H, J=14.3, 7.2).
EXAMPLE 125
[1158]
(2S)-2-Methoxy-3-{4-[2-(4-phenoxy-phenoxy)-acetyl]-phenyl}-propioni-
c acid 230
[1159] The title compound was prepared from a solution of
(2S)-3-[4-(2-Bromo-acetyl)-phenyl]-2-methoxy-propionic acid ethyl
ester (0.076 mmol) from Example 124, Step C in acetonitrile (5 ml).
4-phenoxyphenol (0.152 mmol) and K.sub.2CO.sub.3 (0.23 mmol) were
added. The solution was stirred for 30 min at 80.degree. C. and
then cooled to room temperature. The mixture was concentrated to
dryness under vacuum and chromatographed in silica gel
(hexanes/Ethyl ether 8:2 to 7:3). Fractions corresponding to the
coupled compound were collected (R.sub.f: 0.27) and concentrated to
dryness. The mixture thus obtained was dissolved in 4 mL of NaOH 1N
and 12 mL of Methanol and stirred at room temperature until TLC
indicates the disappearance of starting material. The methanol was
eliminated under vacuum and the aqueous solution diluted with 20 mL
of brine and washed with diethyl ether (3.times.15 mL). The aqueous
phase was acidulated with HCl 1N (until pH 3); extracted with ethyl
acetate (3.times.15 mL) and the organic layer dried (MgSO.sub.4)
and concentrated under vacuum. Obtained a colourless oil.
.sup.1H-NMR (200.15 MHz, CDCl.sub.3): 7.96 (d, 2H, J=8.4),
7.55-7.33 (m, 5H), 7.04-6.83 (m, 6H), 5.24 (s, 2H), 4.08 (dd, 1H,
J=7.4, 4.4), 3.40 (s, 3H), 3.22 (dd, 1H, J=14.3, 4.4), 3.15 (dd,
1H, J=14.3, 7.2).
EXAMPLE 126
[1160]
(2S)-3-{4-[2-(4-Benzoyl-phenoxy)-acetyl]-phenyl}-2-methoxy-propioni-
c acid 231
[1161] The title compound was prepared from a solution of
(2S)-3-[4-(2-Bromo-acetyl) phenyl]-2-methoxy-propionic acid ethyl
ester (0.076 mmol) from Example 124, Step C in acetonitrile (5 ml).
4-hydroxybenzophenone (0.152 mmol) and K.sub.2CO.sub.3 (0.23 mmol)
were added. The solution was stirred for 30 min at 80.degree. C.
and then cooled to room temperature. The mixture was concentrated
to dryness under vacuum and chromatographed in silica gel
(hexanes/Ethyl ether 8:2 to 7:3). Fractions corresponding to the
coupled compound were collected (R.sub.f0.27) and concentrated to
dryness. The mixture thus obtained was dissolved in 4 mL of NaOH 1N
and 12 mL of Methanol and stirred at room temperature until TLC
indicates the disappearance of starting material. The methanol was
eliminated under vacuum and the aqueous solution diluted with 20 mL
of brine and washed with diethyl ether (3.times.15 mL). The aqueous
phase was acidulated with HCl 1N (until pH 3); extracted with ethyl
acetate (3.times.15 ml) and the organic layer dried (MgSO.sub.4)
and concentrated under vacuum. Obtained a colorless oil.
.sup.1H-NMR (200.15 MHz, CDCl.sub.3): 7.96-7.71 (m, 6H), 7.57-7.46
(m, 5H), 6.97 (d, 2H, J=8.1), 5.35 (s, 2H), 4.08 (dd, 1H, J=7.4,
4.2), 3.26 (s, 3H), 3.20 (dd, 1H, J=14.1, 4.1), 3.09 (dd, 1H,
J=14.1, 7.2).
EXAMPLE 127
[1162]
(2S)-3-{4-[3-Biphenyl]-yloxy)-propyl]-phenyl}-2-methoxy-propionic
acid 232
[1163] The title compound was prepared as follows:
(2S)-3-{4-[3-(Biphenyl--
4-yloxy)-prop-1-ynyl]-phenyl}-2-methoxy-propionic acid (O, Step C)
(0.0325 g, 0.08 mmol) was dissolved in methanol (10 mL). Palladium
10% an activated carbon (0.004 g, 0.004 mmol) was added and the
solution saturated with hydrogen (1 Atm) and stirred for 5 hours.
The mixture was filtered through a pad of celite and concentrated
under vacuum. The residue was purified by column chromatography
(silica gel, hexanes/Ethyl acetate-Acetic acid 50:50:1,
R.sub.f0.23) (85%). .sup.1H-NMR (CDCl.sub.3, 200.15 MHz): .delta.
7.56-7.24 (m, 11H), 6.94 (d, 2H, J=8.8), 4.02-3.95 (m, 3H), 3.38
(s, 3H), 3.11 (dd, 1H, J=14.3, 4.4), 2.98 (dd, 1H, J=14.3, 7.3),
2.79 (t, 2H, J=8.1), 2.16-2.03 (m, 3H). MS (ES) for
C.sub.25H.sub.26O.sub.4 [M+NH.sub.4].sup.+: 408.2, [M+Na].sup.+:
413.2.
EXAMPLE 128
[1164]
(2S)-3-{4-[4-(Biphenyl-4-yloxy)-butyl]-phenyl}-2-methoxy-propionic
acid 233
[1165] Step A
[1166] (2S)-3-[4-(4-(4-Hydroxy-butyl)-phenyl]-2-methoxy-propionic
acid ethyl ester 234
[1167]
(2S)-3-[4-(3-Hydroxy-prop-1-ynyl)-phenyl]-2-methoxy-propionic acid
ethyl ester (0.294 g, 1.06 mmol) was dissolved in ethyl acetate (50
mL). Palladium 10% on activated carbon (0.057 g, 0.05 mmol) was
added and the solution saturated with hydrogen (1 Atm) and stirred
for 2 hours. The mixture was filtered through a pad of celite and
concentrated under vacuum. (100%). .sup.1H-NMR (CDCl.sub.3, 200.15
MHz): .delta. 7.12 (dd, 4H, J=11.3, 8.6), 4.17 (q, 2H, J=7.0), 3.94
(dd, 1H, J=7.0, 6.2), 3.65 (t, 2H, J=5.9); 3.35 (s, 3H), 3.00 (s,
1H), 2.97 (s, 1H), 2.61 (t, 2H, J=7.3), 1.73-1.60 (m, 4H), 1.22 (t,
3H, J=7.0).
[1168] Step B
[1169]
(2S)-3-{4-[4-(Biphenyl-4-yloxy)-butyl]-phenyl}-2-methoxy-propionic
acid
[1170] The title compound was prepared from
(2S)-3-[4-(4-Hydroxy-butyl)-ph- enyl]-2-methoxy-propionic acid
ethyl ester and 4-phenylphenol following the Standard Procedure of
coupling-hydrolysis A. .sup.1H-NMR (CDCl.sub.3, 200.15 MHz):
.delta. 7.55-7.23 (m, 7H); 7.14 (d, 4H, J=11.1; 6.93 (d, 2H,
J=68.4); 4.02-3.96 (m, 3H); 3.37 (s, 3H); 3.11 (dd, 1H, J=14.3,
4.4); 2.97 (dd, 1H, J=14.3, 7.3); 2.66 (t, 2H, J=7.0); 1.83-1.80
(m, 4H). MS (ES) for C.sub.26H.sub.28O.sub.4 [M+NH.sub.4].sup.+:
422.2, [M+Na].sup.+: 427.2.
EXAMPLE 129
[1171]
(2S)-3-{4-[5-(Biphenyl-4-yloxy)-pentyl]-phenyl}-2-methoxy-propionic
acid 235
[1172] The title compound was prepared as follows:
(2S)-3-{4-[5-(Biphenyl--
4-yloxy)-pent-1-ynyl]-phenyl}-2-methoxy-propionic acid from Example
21 (0.08 mmol) was dissolved in methanol (10 mL). Palladium 10% on
activated carbon (0.004 g, 0.004 mmol) was added and the solution
saturated with hydrogen (1 Atin) and stirred for 5 hours. The
mixture was filtered through a pad of celite and concentrated under
vacuum. The residue was purified by column chromatography. MS (ES)
for C.sub.27H.sub.30O.sub.4 (M-H].sup.-: 417.3.
EXAMPLE 130
[1173] 3-{4-[3-(4-Benzoyl-phenoxy-propoxy]-3-methoxy-propionic acid
236
[1174] Step A
[1175]
3-(4-Benzyloxy-3-methoxy-phenyl)-3-hydroxy-2-methoxy-propionic acid
methyl ester 237
[1176] A solution of 4-benzyloxy-3-methoxy-benzaldehyde (0.44 g,
1.92 mmol) and methyl methoxyacetate (0.19 mL, 1.92 mmol) in THF
(10 mL) at -78.degree. C. was added dropwise to sodium
bis(trimethylsilyl)amide (20 mL, 2.11 mmol, 1N in THF) at
-78.degree. C. The reaction mixture was stirred for 3 h and
quenched with 1N HCl (5 mL). The mixture was allowed to warm to
room temperature, diluted with water (15 mL), and extracted with
ethyl acetate (3.times.15 mL). The combined organic layers were
dried (MgSO.sub.4) and concentrated. The residue was purified by
silica gel column chromatography (silica gel, hexanes/ethyl
acetate, 1:1) to produce
3-(4-benzyloxy-3-methoxy-phenyl)-3-hydroxy-2-methoxy-propionic acid
methyl ester as an oil (350 mg, 52%); .sup.1H-NMR (200.15 MHz,
CDCl.sub.3): .delta. 7.45-7.20 (m, 5H), 6.9 (s, 1H), 6.8 (b, 2H),
5.1 (s, 2H), 4.90-4.80 (m, 1H), 4.10 (m, 1H), 3.90 (s, 3H), 3.65
(s, 3H), 3.31 (s, 3H), 3.10-2.96 (m, 1H).
[1177] Step B
[1178] 3-(4-Hydroxy-3-methoxy-phenyl-2-methoxy-propionic acid
methyl ester 238
[1179] Trifluoroacetic anhydride (0.62 mL, 4.36 mmol) and
triethylamine (0.62 mL, 4.36 mmol) were added to a solution of
3-(4-benzyloxy-3-methoxy- -phenyl)-3-hydroxy-2-methoxy-propionic
acid methyl ester (1.01 g, 2.91 mmol) in methylene chloride (30 mL)
at 0.degree. C. The resulting mixture was stirred for 4 hours at
room temperature and was concentrated under vacuum. The residue was
dissolved in ethyl acetate (30 mL), and 10% palladium on carbon
(0.3 g) was added to the solution. The mixture was stirred under
hydrogen pressure (4 atm) for 16 hours. The mixture was filtered
through Celite and concentrated under vacuum. The residue was
purified by silica gel column chromatography (silica gel,
hexanes/ethyl acetate 7:3) to produce
3-(4-hydroxy-3-methoxy-phenyl)-2-methoxy-propioni- c acid methyl
ester as an oil (598 mg, 86%). .sup.1H-NMR (200.15 MHz,
CDCl.sub.3): .delta. 6.80 (d, 1H, J=7.8), 6.7 (s, 1H), 6.62 (d, 1H,
J=7.8), 3.96 (dd, 1H, J=7.8, 4.0), 3.80 (s, 3H), 3.68 (s, 3H), 3.30
(s, 3H), 3.09 (dd, 1H, J=14.2, 4.0), 2.91 (dd, 1H, J=14.2,
7.8).
[1180] Step C
[1181] 3-(4-Hydroxy-3-methoxy-phenyl)-2-methoxy-propionic acid
239
[1182] A 1N aqueous lithium hydroxide solution was added to a
solution of 3-(4-hydroxy-3-methoxy-phenyl)-2-methoxy-propionic acid
methyl ester (280 mg, 1.17 mmol) in THF at room temperature, and
the reaction mixture stirred overnight. The aqueous phase was
extracted with ethyl acetate (20 mL), acidified to pH 2, and
extracted with ethyl acetate (3.times.15 mL). The later organic
layers were combined and washed with water (15 mL) and brine (10
mL), dried (MgSO.sub.4), filtered, and concentrated under vacuum to
produce 3-(4-hydroxy-3-methoxy-phenyl)-2-methoxy-propionic acid as
an oil (183 mg, 74%). .sup.1H-NMR (250.13 MHz, CDCl.sub.3): .delta.
6.83 (1H, d, J=7.8), 6.74 (1H, s), 6.72 (1H, d, J=7.8), 3.99 (1H
dd, J=7.8, 4.0), 3.85 (s, 3H), 3.40 (s, 3H), 3.09 (1H, dd, J=14.2,
4.0), 2.91 (1H dd, J=14.2, 7.8).
[1183] Step D
[1184]
3-[4-(tert-Butyl-dimethyl-silanyloxy)-3-methoxy-phenyl)-2-methoxy-p-
ropionic acid 240
[1185] To a solution of
3-(4-hydroxy-3-methoxy-phenyl)-2-methoxy-propionic acid (1.02 g,
4.87 mmol) in CH.sub.2Cl.sub.2-DMF (20 mL=10:1) was added
tert-butyl-dimethylsilyl chloride (1.75 g, 11.68 mmol) and
imidazole (0.70 g, 10.24 mmol). The resulting solution was stirred
at room temperature overnight. Water (15 mL) was added, and the
aqueous phase was extracted with hexanes (30 mL). The hexanes layer
was washed with water (10 mL), dried (MgSO.sub.4), filtered, and
concentrated. The crude product was dissolved in ethyl acetate (10
mL), and a saturated solution of K.sub.2CO.sub.3 (5 mL) was added.
The resulting mixture was stirred for 2 hours at room temperature.
The aqueous layer was extracted with ethyl acetate (10 mL),
acidified to pH 3, and extracted again with ethyl acetate
(3.times.10 mL). The later organic layers were combined and washed
with brine (20 mL), dried (MgSO.sub.4), and concentrated to a
yellow oil (1.2 g, 77%). .sup.1H-NMR (200.15 MHz, CDCl.sub.3):
.delta. 6.78-6.67 (m, 3H), 3.96 (dd, 1H, J=7.8, 4.0), 3.78 (s, 3H),
3.35 (s, 3H), 3.09 (dd, 1H, J=14.2, 4.0), 2.91 (dd, 1H, J=114.2,
7.8), 0.98 (s, 9H), 0.13 (6H, s).
[1186] Step E
[1187] Preparation of
3-[4-(tert-Butyl-dimethyl-silanyloxy)-3-methoxy-phen-
yl]-2-methoxy-propionic acid linked to Wang's Resin 241
[1188] The title compound was prepared following the procedure as
in Example 95, Step B.
[1189] Step F
[1190] Preparation of
3-(4-hydroxy-3-methoxy-phenyl)-2-methoxy-propionic acid linked to
Wang's Resin 242
[1191] The title compound was prepared following the procedure as
in Example 95, Step C.
[1192] Step G
[1193] Preparation of
3-[4-(3-hydroxy-propoxy)-3-methoxy-phenyl]-2-methoxy- -propionic
acid linked to Wang's Resin. 243
[1194] The title compound was prepared from
3-(4-hydroxy-3-methoxy-phenyl)- -2-methoxy-propionic acid linked to
Wang's Resin via Mitsunobu coupling (Standard Procedure F) to
produce 3-[4-(3-hydroxy-propoxy)-3-methoxy-phen-
yl]-2-methoxy-propionic acid linked to Wang's Resin.
[1195] Step H
[1196]
3-{4-[3-(4-Benzoyl-phenoxy)-propoxy]-3-methoxy-phenyl}-2-methoxy-pr-
opionic acid 244
[1197] The title compound was prepared from
3-(4-(3-hydroxy-propoxy)-3-met- hoxy-phenyl)-2-methoxy-propionic
acid linked to Wang's Resin via the Mitsunobu coupling-cleavage
from the resin procedure (Standard Procedure G) to produce an oily
solid (4%). .sup.1H-NMR (200.15 MHz, CDCl.sub.3): .delta. 7.81-7.72
(m, 4H), 7.57-7.43 (m, 3H), 6.96 (d, 2H, J=8.9), 6.81-6.73 (m, 3H),
4.28 (t, 2H, J=6.2), 4.20 (t, 2H, J=6.2), 4.01 (dd, 1H, J=7.0,
4.6), 3.83 (s, 3H), 3.42 (s, 3H), 3.09 (dd, 1H, J=14.5, 4.0), 2.97
(dd, 1H, J=14.5, 7.0), 2.33 (qn, 2H, J=6.2).
EXAMPLE 131
[1198]
3-(4-{3-[4-(4-Fluoro-benzoyl)-phenoxy]-propoxy}-3-methoxy-phenyl-2--
methoxy-propionic acid 245
[1199] The title compound was prepared from
3-(4-(3-hydroxy-propoxy)-3-met- hoxy phenyl)-2-methoxy-propionic
acid linked to Wang's Resin via the Mitsunobu coupling-cleavage
from the resin procedure (Standard Procedure G) to produce an oily
solid (4%). .sup.1H-NMR (200.15 MHz, CDCl.sub.3): .delta. 7.83-7.74
(m, 4H), 7.15 (t, 2H, J=8.6 Hz), 6.96 (d, 2H, J=8.6), 6.85-6.74 (m,
3H), 4.28 (t, 2H, J=6.2), 4.20 (t, 2H, J=6.2), 4.01 (dd, 1H, J=7.0,
4.6), 3.84 (s, 3H), 3.42 (s, 3H), 3.10 (dd, 1H, J=14.2, 4.6), 2.97
(dd, 1H, J=14.2, 7.0), 2.33 (qn, 2H, J=6.2).
EXAMPLE 132
[1200]
3-{4-[3-(Biphenyl-4-yloxy)-propoxy]-3-methoxy-phenyl}-2-methoxy-pro-
pionic acid 246
[1201] Step A
[1202] 3-(4-Hydroxy-3-methoxy-phenyl)-2-methoxy-propionic acid
ethyl ester 247
[1203] To a solution of
3-[4-(tert-butyl-dimethyl-silanyloxy)-3-methoxy-ph-
enyl]-2-methoxy-propionic acid (356 mg, 1.05 mmol) in absolute
ethanol (1 mL) was added concentrated sulfuric acid (0.033 mL, 0.63
mmol). The reaction mixture was allowed to stir at room temperature
for 17 hours. The solution was concentrated under vacuum, and water
(10 mL) and solid NaHCO.sub.3 were added to neutralize the residue.
The aqueous phase was extracted with ethyl acetate (2.times.10 mL).
The combined organic layers were washed with water (20 mL) and
brine (20 mL), dried (MgSO.sub.4), filtered, and concentrated to
produce 3-(4-hydroxy-3-methoxy-phenyl)-2-me- thoxy-propionic acid
ethyl ester (260 mg, 98%). .sup.1H-NMR (200.15 MHz, CDCl.sub.3):
.delta. 6.83 (d, 1H, J=8.1 Hz), 6.76-6.69 (m, 2H), 4.19 (q, 2H,
J=7.3 Hz), 3.97-3.90 (m, 1H), 3.87 (s, 3H), 3.36 (s, 3H), 2.96-2.92
(m, 2H), 1.25 (t, 3H, J=7.3 Hz).
[1204] Step B
[1205] [1,3,2]Dioxathiane 2,2-dioxide 248
[1206] To a solution of 1,3-propanodiol (30 g, 394 mmol) in
CCl.sub.4 (278 mL) was added thionyl chloride (36 mL, 491 mmol) via
syringe. The resulting mixture was heated at reflux for 1.5 h and
was cooled to 0.degree. C. to evaporate the solvent under vacuum.
The residue was dissolved in a mixture of
CCl.sub.4/CH.sub.3CN/H.sub.2O (2:2:3=500 mL) and cooled to
0.degree. C. Ruthenium trichloride trihydrate (0.556 g, 2.68 mmol)
was added, followed by addition of solid NaIO.sub.4 (14.35 g, 197
mmol). The mixture was stirred at room temperature for 1 h,
H.sub.2O (1 L) was added, and the aqueous phase was extracted with
diethyl ether (4.times.300 mL). The combined organic layers were
washed with brine (2.times.100 mL), dried (MgSO.sub.4), and
filtered through a pad of silica gel to remove the ruthenium salts.
The solvent was evaporated and hexanes (200 mL) was added to the
resulting oil. After cooling, a gray solid precipitated. The solid
was filtered and washed with hexanes. Recrystallization from
hexanes/ether yielded a white, crystalline solid (18.15 g, 33%).
.sup.1H-NMR (200.15 MHz, CDCl.sub.3): .delta. 4.73 (t, 1H, J=5.6),
2.13 (qn, 2H, J=5.6).
[1207] Step C
[1208] 3-(Biphenylyloxy)-propan-1-ol 249
[1209] A solution of 4-phenylphenol (4.9 g, 29.0 mmol) and
potassium tert-butoxide (3.64 g, 30.3 mmol) in THF (100 mL) was
stirred at room temperature for 30 min. The solution was cooled at
0.degree. C. and [1,3,2]dioxathiane 2,2-dioxide (3.6 g, 26.34 mmol)
in THF (25 mL) was added. The resulting mixture was stirred at room
temperature for 5 hours, and the solvent was removed under vacuum.
The residue was dissolved in 6N HCl (15 mL) and heated at
100.degree. C. for 16 hours. The mixture was cooled to room
temperature, and the aqueous phase was extracted with ethyl acetate
(3.times.30 mL). The combined organic layers were washed with
H.sub.2O (3.times.25 mL) and brine (25 mL), dried (MgSO.sub.4),
filtered, and concentrated to produce
3-(biphenyl-4-yloxy)-propan-1-ol as a white solid (4.16 gi 63%).
.sup.1H-NMR (200.15 MHz, CDCl.sub.3): .delta. 7.57-7.49 (m, 4H),
7.45-7.37 (m, 3H), 6.98 (dd, 2H, J=6.72, 2.14), 4.17 (t, 2H,
J=5.9), 3.88 (q, 2H, J=5.9), 2.07 (qn, 2H, J=5.9).
[1210] Step D
[1211] 4-(3-Bromo-propoxy)-biphenyl 250
[1212] To a solution of 3-(biphenyl-4-yloxy)-propan-1-ol (1.00 g,
4.38 mmol) in CH.sub.2Cl.sub.2 (20 mL) at 0.degree. C. was added
triphenylphosphine (1.61 g, 6.14 mmol) and carbon tetrabromide
(1.81 g, 5.47 mmol). The reaction mixture was allowed to warm to
room temperature, stirred for 1 hour, and extracted with ethyl
acetate (50 mL). The organic layer was washed with H.sub.2O
(3.times.50 mL) and bine (3.times.25 mL), dried (MgSO4), filtered
and concentrated. The crude product was purified by silica gel
column chromatography (silica gel, hexanes/ethyl acetate, 9:1) to
produce 4-(3-bromo-propoxy)-biphenyl (1.22 g, 95%). .sup.1H-NMR
(200.15 MHz, CDCl.sub.3): .delta. 7.57-7.29 (m, 7H), 6.98 (dd, 2H,
J=6.72, 1.88), 4.15 (t, 2H, J=5.92), 3.62 (t, 2H, J=6.44), 2.34
(qn, 2H, J=5.92).
[1213] Step E
[1214]
3-{4-[3-(Biphenyl-4-yloxy)-propoxy]-3-methoxy-phenyl}-2-methoxy-pro-
pionic acid ethyl ester 251
[1215] To a solution of
3-(4-hydroxy-3-methoxy-phenyl)-2-methoxy-propionic acid ethyl ester
(Example 132, Step A) (0.080 g, 0.31 mmol) in acetonitrile (10 mL)
was added 4-(3-bromo-propoxy)biphenyl (Example 132, Step D) (0.101
g, 0.35 mmol) and potassium carbonate (0.115 g, 0.945 mmol). The
resulting suspension was stirred at 85.degree. C. overnight. After
cooling, the reaction mixture was diluted with ethyl acetate (10
mL), and water (10 mL) was added. The organic layer was washed with
water (10 mL) and brine (10 mL), dried (MgSO.sub.4), and
concentrated. The crude product was purified by silica gel column
chromatography (silica gel, hexanes/ethyl acetate, 7:3) to produce
3-{4-[3-(biphenyl-4-yloxy)-pr-
opoxy]-3-methoxy-phenyl}-2-methoxy-propionic acid ethyl ester
(0.086 g, 59%). .sup.1H-NMR (200.15 MHz, CDCl.sub.3): .delta.
7.57-7.26 (m, 7H), 6.98 (d, 2H, J=8.6), 6.87-6.73 (m, 3H),
4.25-4.17 (m, 6H), 3.91 (dd, 1H, J=7.0, 5.6), 3.83 (s, 3H), 3.35
(s, 3H), 2.97-2.93 (m, 2H), 2.31 (qn, 2H, J=5.9), 1.24 (t, 3H,
J=7.3).
[1216] Step F
[1217]
3-{4-[3-(Biphenyl-4-yloxy)-propoxy]-3-methoxy-phenyl}-2-methoxy-pro-
pionic acid
[1218] The title compound was prepared from 3-{4-[3
(biphenyl-4-yloxy)-propoxy]-3-methoxy-phenyl}-2-methoxy-propionic
acid ethyl ester following the hydrolysis procedure described in
Example 130, Step C. .sup.1H-NMR (200.15 MHz, CDCl.sub.3): .delta.
7.56-7.25 (m, 7H), 6.97 (d, 2H, J=8.9), 6.89-6.79 (m, 3H), 5.07 (b,
1H), 4.17 (q, 4H, J=5.6), 3.95 (dd, 1H, J=7.5, 3.5), 3.82 (s, 3H),
3.32 (s, 3H), 3.11-2.86 (m, 2H), 2.28 (qn, 2H, J=6.2).
EXAMPLE 133
[1219]
2-Methoxy-3-{3-methoxy-{3-(4-phenoxy-phenoxy)-propoxy]-phenyl}-prop-
ionic acid 252
[1220] The title compound was prepared following the procedure
described for Example 132 (Steps A-E). .sup.1H-NMR (200.15 MHz,
CDCl.sub.3): .delta. 7.32-7.24 (m, 2H), 7.06-6.75 (m, 10H), 4.16
(q, 4H, J=6.2), 3.97 (dd, 1H, J=7.8, 4.3), 3.82 (s, 3H), 3.37 (s,
3H), 3.08 (dd, 1H, J=14.2, 4.0), 2.94 (dd, 1H, J=14.5, 7.8); 2.27
(qn, 2H, J=6.2).
EXAMPLE 134
[1221]
(2S)-3-(4-[3-(Biphenyl-4-yloxy)-propoxy]-3-chloro-phenyl}-2-methoxy-
-propionic acid 253
[1222] Step A
[1223] (2S)-3-(3-Chloro-4-hydroxy-phenyl)-2-methoxy-propionic acid
ethyl ester 254
[1224] To a solution of 3-(4-hydroxy-phenyl)-2-methoxy-propionic
acid ethyl ester (0.113 g, 0.5 mmol) in CH.sub.3CN (3 mL) cooled to
0.degree. C., N-chlorosuccinimide (0.067 g 0.5 mmol,) was added in
various portions. The mixture was allowed to warm to room
temperature and was stirred for 8 hours. The mixture-was
concentrated under vacuum, and the resulting oil was washed with
CCl.sub.4 (4 mL). The precipitate which formed was filtered, and
the filtrate was concentrated to give a mixture of
3-(3-chloro-4-hydroxy-phenyl)-2-methoxy-propionic acid ethyl ester
and 3-(3,5-Dichloro-4-hydroxy-phenyl)-2-methoxy-propionic acid
ethyl ester as a brown oil which was purified by
ultraviolet-directed HPLC. A colorless oil was obtained (0.020 g,
14%). .sup.1H-NMR (200.15 MHz, CDCl.sub.3): .delta. 7.18 (d, 1H,
J=2.15), 7.02 (dd, 1H, J=8.32, 2.15), 6.91 (d, 1H, J=8.32), 4.18
(q, 2H, J=7.25), 3.88 (dd, 1H, J=7.24, 5.62), 3.35 (s, 3H), 2.92
(dd, 2H, J=6.31, 2.42), 1.24 (t, 3H, J=7.2).
[1225] Step B
[1226]
(2S)-3-{4-[3-(Biphenyl-4-yloxy)-propoxy]-3-chloro-phenyl}-2-methoxy-
-propionic acid ethyl ester 255
[1227] 3-(3 Chloro-4-hydroxy-phenyl)-2-methoxy-propionic acid ethyl
ester (0.020 g, 0.077 mmol) was dissolved in CH.sub.3CN (3 mL) and
4-(3-bromo-propoxy)-biphenyl (Example 132, Step D), (0.025 g 0.085
mmol) and K.sub.2CO.sub.3 (0.032 g, 0.23 mmol) were added. The
mixture was heated to 85.degree. C. and stirred for 5 hours. After
cooling, water (2 mL) was added. The mixture was extracted in EtOAc
(3.times.10 mL), washed with H.sub.2O (2.times.5 mL) and brine
(2.times.5 mL). The organic layer was dried (MgSO.sub.4), filtered,
and concentrated in vacuo. The crude product was purified by silica
gel column chromatography (silica gel, hexanes/ethyl acetate 9:1)
to produce 3-{4-[3-(Biphenyl-4-yloxy)-propoxy]-
-3-chloro-phenyl}-2-methoxy-propionic acid ethyl ester (0.017 mg,
48%). .sup.1H-NMR (200.15 MHz, CDCl.sub.3): .delta. 7.57-7.24 (m,
9H), 7.02-6.89 (m, 3H), 4.28-4.12 (m, 5H), 3.89 (dd, 1H, J=7.24,
5.62), 3.62 (t, 1H, J=6.44), 3.36 (s, 3H), 2.93 (dd, 2H, J=6.31,
2.42), 2.32 (qn, 2H, J=5.10), 1.25 (t, 3H, J=7.2).
[1228] Step C
[1229]
(2S)-3-{4-[3-(Biphenyl-4-yloxy)-propoxy]-3-chloro-phenyl}-2-methoxy-
-propionic acid
[1230] The title compound was prepared as follows:
3-{4-[3-(Biphenyl-4-ylo-
xy)-propoxy]-3-chloro-phenyl}-2-methoxy-propionic acid ethyl ester
(0.017 g, 0.037 mmol) was dissolved in 0.25 M ethanolic NaOH
solution (0.3 mL, 0.075 mmol). The mixture was stirred 16 hours at
room temperature and water was added. The aqueous layer was
extracted with Et.sub.2O (3.times.5 mL). The aqueous layer was
acidified to pH=1 with 1 N HCl and extracted with Et.sub.2O
(5.times.10 mL). The organic layer was dried (MgSO.sub.4) and
concentrated under vacuum to give the title compound as a yellow
oil (0.006 mg, 38%). .sup.1H-NMR (200.15 MHz, CDCl.sub.3): .delta.
7.57-7.25 (m, 9H), 7.0-6.86 (m, 3H), 4.23 (q, 4H, J=6.18), 3.96
(dd, 1H, J=7.24, 4.28), 3.40 (s, 3H), 3.06 (dd, 1H, J=14.5, 4.28),
2.92 (dd, 1H, J=14.5, 7.24), 2.32 (qn, 2H, J=5.92).
EXAMPLE 135
[1231]
3-3-Chloro-4-[3-(4-phenoxy-phenoxy)-propoxy]-phenyl}-2-methoxy-prop-
ionic acid 256
[1232] The title compound was prepared as a same manner in Example
134, but using 43-bromopropoxy)-1-phenoxybenzene as material for
the coupling reaction
EXAMPLE 136
[1233]
'3-{4-[3-(4-Benzoyl-phenoxy)-propoxy]-3-chloro-phenyl}-2-methoxy-pr-
opionic acid 257
[1234] The title compound was prepared as a same manner in Example
134, but using [4-(3-Bromo-propoxy)-phenyl]-phenyl-methanoneas
material for the coupling reaction
EXAMPLE 137
[1235]
3-{4-[3-(Biphenyl-4-yloxy)-propoxy]-3,5-dichloro-phenyl}-2-methoxy--
propionic acid 258
[1236] Step A
[1237] 3-{4-[3,5-Dichloro-4-hydroxy-phenyl)-2-methoxy-propionic
acid ethyl ester
[1238] To a solution of 3-(4-hydroxy-phenyl)-2-methoxy-propionic
acid ethyl ester (0.113 g, 0.5 mmol) in CH.sub.3CN (3 mL) cooled to
0.degree. C., N-chlorosuccinimide (0.067 g, 0.5 mmol,) was added in
various portions. The mixture was allowed to warm to room
temperature and was stirred for 8 hours. The mixture was
concentrated under vacuum, and the resulting oil was washed with
CCl.sub.4 (4 mL). The precipitate which formed was filtered and the
filtrate was concentrated to give a mixture of
3-(3-chloro-4-hydroxy-phenyl)-2-methoxy-propionic acid ethyl ester
and 3-(3,5-Dichloro-4-hydroxy-phenyl)-2-methoxy-propionic acid
ethyl ester as a brown oil which was purified by
ultraviolet-directed HPLC.
[1239] Step B
[1240]
3-{4-[3-(Biphenyl-4-yloxy)-propoxy]-3,5-dichloro-phenyl}-2-methoxy--
propionic acid
[1241] The title compound was prepared staring from compound from
Step A and using the same procedure as in 0.
EXAMPLE 138
[1242]
3-{4-[3-(Biphenyl-4-yloxy)-propoxy]-3-fluoro-phenyl}-2-methoxy-prop-
ionic acid 259
[1243] Step A
[1244] 2-(3-Fluoro-4-methoxy-phenyl-[1,3]-dioxolane 260
[1245] A solution of 3-fluoro-4-methoxy-benzaldehyde (463 mg, 3
mmol), ethylene glycol (0.86 mL, 15 mmol) and PPTs (75 mg, 0.3
mmol) in toluene (15 mL) was heated at reflux with aceotropic
removal of water for 6 hours. The solvent was evaporated and the
residue was diluted with methylene chloride (20 mL), washed with
water (2.times.10 mL) and dried (MgSO.sub.4). Concentration
produced 2-(3-Fluoro-4-methoxy-phenyl)-[1,3]-- dioxolane as a
colorless oil (550 mg, 92%). .sup.1H-NMR (CDCl.sub.3, 200.15 MHz):
.delta. 7.24-7.15 (m, 2H), 6.92 (t, 1H, J=8.5), 5.71 (s, 1H),
4.10-3.98 (m, 4H), 3.86 (s, 3H).
[1246] Step B
[1247] 4-[1,3]Dioxolan-2-yl-2-fluorophenol 261
[1248] A solution of 2-(3-Fluoro-4-methoxy-phenyl)-[1,3]-dioxolane
(250 mg, 1.26 mmol) and Sodium thiomethoxide (106 mg, 1.51 mmol) in
dry N,N-dimethylformamide (3.5 mL) was heated at 100.degree. C.
under nitrogen for 4 hours. Then a saturated solution of ammonium
chloride (15 mL) was added and the aqueous layer extracted with
methylene chloride (4.times.10 mL). The combined organic layers
were dried (Na.sub.2SO.sub.4), filtered and concentrated under
vacuum. The residue was chromatographed (silica gel, hexanes/ethyl
acetate 7:3) to produce 4-[1,3]dioxolan-2-yl-2-fluoro-phenol as a
pale brown oil (120 mg, 52%). .sup.1H-NMR (CDCl.sub.3, 200.15 MHz):
.delta. 7.24-7.01 (m, 2H), 6.88 (t, 1H, J=8.4), 6.07 (s, 1H), 5.71
(s, 1H), 4.13-3.95 (m, 4H).
[1249] Step C
[1250] 3-Fluoro-4-hydroxy-benzaldehyde 262
[1251] A solution of 1N HCl (1 mL) and
4-[1,3]dioxolan-2-yl-2-fluoro-pheno- l (250 mg, 1.35 mmol) in THF
(2 mL) was stirred, at room temperature for 1 hour. The mixture was
diluted with water and extracted with methylene chloride
(4.times.10 mL). The combined organic layers were dried
(Na.sub.2SO.sub.4), filtered and concentrated under vacuum. The
residue was chromatographed (silica gel, hexanes/ethyl acetate 1:1)
to produce 3-Fluoro-4-hydroxy-benzaldehyde as a white solid (180
mg, 95%). .sup.1H-NMR (CDCl.sub.3, 200.15 MHz): 9.84 (d, 1H,
J=2.4), 7.68-7.59 (m, 2H), 7.15 (t, 1H, J=8.5), 6.5 (s, 1H).
[1252] Step D
[1253] 4-[3-(Biphenyl-4-yloxy)-propoxy]-3-fluoro-benzaldehyde
263
[1254] Potassium tert-butoxide (198 mg, 1.76 mmol) was added, at
0.degree. C., to a solution of 3-Fluoro-4-hydroxy-benzaldehyde (235
mg, 1.68 mmol) in dry N,N-dimethylformamide (2 mL). The mixture was
stirred for 10 minutes. 4-(3-Bromo-propoxy)-biphenyl (example 23,
Step D) (539 mg, 1.84 mmol) was added and the reaction was stirred
for 24 hours at room temperature. The mixture was diluted with
water (15 mL) and extracted with ethyl acetate (4.times.15 mL). The
combined organic layers were dried (Na.sub.2SO.sub.4), filtered,
and concentrated under vacuum to produce a solid which was washed
with hexanes to produce
4-[3-(Biphenyl-4-yloxy)-propoxy]-3-fluoro-benzaldehyde as a pale
brown solid (490 mg, 83%). .sup.1H-NMR (CDCl.sub.3, 200.15 MHz):
.delta. 9.83 (d, 1H, J=2.2), 7.64-7.23 (m, 9H), 7.09 (t, 1H,
J=8.2), 6.96 (d, 2H, J=8.8), 4.32 (t, 2H, J=5.9), 4.21 (t, 2H,
J=5.9), 2.35 (qn, 2H, J=5.9).
[1255] Step E
[1256]
3-{4-[3-(Biphenyl-4-yloxy)-propoxy]-3-fluoro-phenyl}-3-hidroxy-2-me-
thoxy-propionic acid methyl ester 264
[1257] To a solution of sodium bis(trimethylsilyl)amide 1N (0.71
mL, 0.71 mmol) in dry THF (5 mL), was added dropwise methyl
methoxyacetate (57 .mu.L, 0.57 mmol) at -78.degree. C. The solution
was stirred for 1 hour.
4-[3-(Biphenyl-4-yloxy)-propoxy]-3-fluoro-benzaldehyde (220 mg,
0.626 mmol) was added and the mixture warmed to 0.degree. C. and
stirred for 3 additional hours. The mixture was quenched with 1N
HCl (2 mL), diluted with water (20 mL) and extracted with
dichloromethane (4.times.15 mL). The combined organic layers were
dried (Na.sub.2SO.sub.4), filtered and concentrated under vacuum.
The residue was chromatographed (silica gel, hexanes/ethyl acetate
7:3) to produce 3-{4-[3-(Biphenyl-4-yloxy)-propoxy]-
-3-fluoro-phenyl}-3-hidroxy-2-methoxy-propionic acid methyl ester
as a colourless oil (62 mg, 24%). .sup.1H-NMR (CDCl3, 200.15 MHz):
.delta. 7.55-7.25 (m, 8H), 7.15-6.89 (m, 5H), 4.91-4.79 (m, 1H),
4.24-4.18 (m, 4H), 3.92 and 3.81 (2d, 1H, J=5.86 and 5.48), 3.67
and 3.64 (2s, 3H), 3.40 and 3.36 (2s, 3H), 3.01 and 2.94 (2d, 1H,
5.12 and 5.12), 2.29 (qn, 2H, J=5.9).
[1258] Step F
[1259]
3-{4-[3-(Biphenyl-4-yloxy)-propoxy]-3-fluoro-phenyl}-2-methoxy-prop-
ionic acid methyl ester 265
[1260] Trifluoroacetic anhydride (0.056 mL, 0.395 mmol) and
pyridine (0.048 mL, 18.9 mmol) were added to a solution of
3-{4-[3-(Biphenyl-4-ylo-
xy)-propoxy]-3-fluoro-phenyl}-3-hidroxy-2-methoxy-propionic acid
methyl ester (90 mg, 0.197 mmol) in methylene chloride (2; mL) at
0.degree. C. The mix was stirred for 4 hours at room temperature
and quenched with 1N HCl (10 mL). The layers were separated and the
aqueous extracted with methylene chloride (3.times.20 mL). The
combined organic layers were evaporated and the residue dissolved
in ethyl acetate (50 mL). 10% palladium on carbon (90 mg) was added
to the solution and mixture was stirred under hydrogen pressure (5
atm) for 16 hours, filtered through a pad of celite and
concentrated under vacuum. The residue was chromatographed (silica
gel, hexanes/ethyl acetate 4:1) to produce
3-{4-[3-(Biphenyl-4-yloxy)-propoxy]-3-fluorophenyl}-2-methoxy-propionic
acid methyl ester as a colorless oil (40 mg, 46%). .sup.1H-NMR
(CDCl.sub.3, 200.15 MHz): .delta. 7.58-7.49 (m, 4H), 7.46-7.37 (m,
2H), 7.34-7.24 (m, 1H), 7.01-6.90 (m, 5H), 4.22 (t, 4H, J=5.9),
3.93 (dd, 1H, J=7.3, 5.3), 3.73 (s, 3H), 3.37 (s, 3H), 2.97-2.92
(m, 2H), 2.31 (qn, 2H, J=5.9).
[1261] Step G
[1262]
3-{4-[3-(Biphenyl-4-yloxy)-propoxy]-3-fluoro-phenyl}-2-methoxy-prop-
ionic acid
[1263] The title compound was prepared from
3-{4-[3-(Biphenyl-4-yloxy)-pro-
poxy]-3-fluoro-phenyl}-2-methoxy-propionic acid methyl ester
following the Standard Procedure E: white solid (38 mg, 98%).
.sup.1H-NMR (CDCl.sub.3, 200.15 MHz): .delta. 7.58-7.49 (m, 4H),
7.46-7.37 (m, 2H), 7.34-7.24 (m, 1H), 7.01-6.90 (m, 5H), 4.23 (t,
2H, J=5.9), 4.22 (t, 2H, J=5.9), 3.97 (dd, 1H, J=7.4, 4.4), 3.4 (s,
3H), 3.12-2.89 (m, 2H), 2.31 (qn, 2H, J=5.9).
EXAMPLE 139
[1264]
3-{4-[3-(Biphenyl-4-yloxy)-propoxy]-3-trifluoromethyl-phenyl}-2-met-
hoxy-propionic acid 266
[1265] Step A
[1266] 3-Bromo-4-hydroxy-benzaldehyde 267
[1267] A solution of bromine (0.88 mL, 17.18 mmol) in chloroform
(20 mL) was added dropwise at room temperature to a solution of
4-hydroxybenzaldehyde (2 g, 16.36 mmol) in chloroform (40 mL) and
the mixture was stirred for 0.5 hour at room temperature and 1 more
hour at 40.degree. C. A saturated solution of NaHCO.sub.3 (30 mL)
was added and the organic layer separated. The aqueous layer was
extracted with methylene chloride (3.times.20 mL). Thee combined
organic layers were dried (Na.sub.2SO.sub.4), filtered and
concentrated under vacuum. The residue was chromatographed (silica
gel, methylene chloride-methanol 98:2) to affored
3-Bromo-4-hydroxy-benzaldehyde as a white solid (1.1 g, 34%).
.sup.1H-NMR (CDCl.sub.3, 200.15 MHz): 9.80 (s, 1H), 8.02 (d, 1H,
J=1.8), 7.75 (dd, 1H, J=8.4, 1.8), 7.12 (d,
[1268] Step B
[1269] 4-Benzyloxy-3-bromo-benzaldehyde 268
[1270] 3-Bromo-4-hydroxy-benzaldehyde (1.9 g, 9.45 mmol) was added
slowly, at 0.degree. C., to a suspension of NaH 95% (290 mg, 11.34
nol) in dry N,N-dimethylformamide (45 mL). The mixture was stirred
for 0.5 hours. Benzyl chloride (1.3 mL, 11.34 mmol) was added and
the reaction stirred at room temperature overnight. 1N HCl (40 mL)
was added and the layers separated. The aqueous layer was extracted
with diethyl ether (5.times.50 mL) and the combined organic layers
were dried (Na.sub.2SO.sub.4), filtered, and concentrated under
vacuum. The residue was chromatographed (silica gel, hexanes/ethyl
acetate 9:1) to produce 4-Benzyloxy-3-bromo-benzaldehyde as a white
solid (2.47 g, 90%). .sup.1H-NMR (CDCl.sub.3, 200.15 MHz): .delta.
9.82 (s, 1H), 8.09 (d, 1H, J=1.8), 7.76 (dd, 1H, J=8.4, 1.8),
7.47-7.32 (m, 5H), 7.02 (d, 1H, J=8.4), 5.24 (s, 2H.
[1271] Step C
[1272] 4-Benzyloxy-3-trifluoromethyl-benzaldehyde 269
[1273] Methyl 2,2-difluoro-2-(fluorosulfonyl)-acetate (1.25 mL,
9.78 mmol) was added to a suspension of dry CuI (745 mg, 3.91 mmol)
and 4-Benzyloxy-3-bromo-benzaldehyde (570 mg, 1.96 mmol) in dry
N,N-dimethylformamide (10 mL). The mixture was stirred under
nitrogen at 120.degree. C. for 6 hours in a sealed tube. The
reaction mixture was cooled to room temperature and diluted with
water (20 mL). The aqueous layer was extracted with diethyl ether
(4.times.20 mL) and the combined organic layers were dried
(Na.sub.2SO.sub.4), filtered and concentrated under vacuum. The
residue was chromatographed (silica gel, hexanes/ethyl acetate 9:1)
to produce 4 Benzyloxy-3-trifluoromethyl-benzaldehyde as a white
solid (120 mg, 22%). .sup.1H-NMR (CDCl.sub.3, 200.15 MHz): .delta.
9.88 (s, 1H), 8.11 (d, 1H, J=1.8), 7.98 (dd, 1H, J=8.6, 1.8),
7.44-7.31 (m, 5H), 7.14 (d, 1H, J=8.6), 5.27 (s, 2H).
[1274] Step D
[1275] 3-(4-hydroxy-3-trifluoromethyl-phenyl)-2-methoxy-acrylic
acid methyl ester 270
[1276] To a solution of sodium bis(trimethylsilyl)amide 1N (0.8 mL,
0.8 mmol) in THF (4 mL), was added dropwise methyl methoxyacetate
(0.066 mL, 0.66 mmol) at -78.degree. C. After allowing the mixture
to stir for 1 hour, 4-Benzyloxy-3-trifluoromethyl-benzaldehyde (185
mL, 0.66 mmol) was added dropwise. When the addition was finished
the mixture was warmed to room temperature and stirred for 3
additional hours. Trifluoroacetic anhydride (0.28 mL, 1.98 mmol)
was added and the mixture was stirred at room temperature for 4
hours. The solvent was evaporated and the residue dissolved in
ethyl acetate (50 mL). 10% palladium on carbon (200 mg) was added
to the solution and the mixture stirred under hydrogen pressure (5
atm) for 16 hours, filtered through a pad of celite and
concentrated under vacuum. The residue was chromatographed (silica
gel, hexanes/ethyl acetate 4:1) to produce 3-(4
hydroxy-3-trifluoromethyl-phenyl)-2-methoxy-- acrylic acid methyl
ester as a white solid (72 mg, 40%). .sup.1H-NMR
((CD.sub.3).sub.2CO, 200.15 MHz): .delta. 9.65 (b, 1H), 8.02 (d,
1H, J=1.8), 7.87 (dd, 1H, J=8.4, 1.8), 7.08 (d, 1H, J=8.4), 6.90
(s, Il), 3.77 (s, 3H), 3.75 (s, 3H).
[1277] Step E
[1278]
3-{4-[3-(biphenyl-4-yloxy)-propoxy]-3-trifluoromethyl-phenyl}-2-met-
hoxy-acrylic acid methyl ester 271
[1279] Potassium tert-butoxide (15 mg, 0.13 mmol) was added at
0.degree. C. to a solution of
3-(4-hydroxy-3-trifluoromethyl-phenyl)-2-methoxy-acry- lic acid
methyl ester (35 mg, 0.126 mmol) in dry N,N-dimethylformamide (0.6
mL). The mixture was stirred for 0.5 hours and
4-(3-Bromo-propoxy)-biphenyl (example 23, Step D) (45 mg, 0.15
mmol) was added. The reaction was stirred for 6 hours at room
temperature and quenched with a saturated solution of ammonium
chloride (10 mL). The aqueous layer was separated and extracted
with methylene chloride (5.times.10 mL). The combined organic
layers were dried (Na.sub.2SO.sub.4), filtered and concentrated
under vacuum. The residue was chromatographed (silica gel,
hexanes/ethyl acetate 8:2) to produce
3-{4-[3-(biphenyl-4-yloxy)-propoxy]-3-fluoromethyl-phenyl}-2-methoxy-acry-
lic acid methyl ester as a colorless oil (35 mg, 57%). .sup.1H-NMR
(CDCl.sub.3, 200.15 MHz): .delta. 8.00 (d, 1H, J=1.6), 7.89 (dd,
1H, J=8.6, 1.6), 7.46-7.26 (m, 7H), 7.05-6.93 (m, 4H), 4.33-4.20
(m, 4H), 3.86 (s, 3H), 3.79 (s, 3H), 2.33 (qn, 2H, J=5.9).
[1280] Step F
[1281]
3-[4-3-biphenylyloxy)-propoxy]-3-trifluoromethyl-phenyl]-2-methoxy--
acrylic acid 272
[1282] The title compound was prepared
3-{4-[3-(biphenyl-4-yloxy)-propoxy]-
-3-trifluoromethyl-phenyl}-2-methoxy-acrylic acid methyl ester (35
mg, 0.072 mmol) following the Standard Procedure E: white solid (31
mg, 92%). .sup.1H-NMR (CDCl3, 200.15 MHz): 58.02 (d, 1H, J=1.8),
7.88 (dd, 1H, J=8.6, 1.8), 7.57-7.28 (m, 7H), 7.08-6.96 (m, 4H),
4.35-4.21 (m, 4H), 3.81 (s, 3H), 2.34 (qn, 2H, J=5.8).
[1283] Step G
[1284]
3-{4-[3-(biphenyl-4-yloxy)-propoxy]-3-trifluoromethoxy-phenyl}-2-me-
thoxy-propionic acid
[1285] The title compound was prepared as follows: A mixture of
3-{4-[3-(biphenyl-4-yloxy)-propoxy]-3-trifluoromethyl-phenyl}-2-methoxy-a-
crylic (20 mg, 0.041 mmol) and magnesium (20 mg, 0.82 mmol) in
methanol (1 mL) was stirred at room temperature for 80 hours. The
reaction mixture was quenched with 1N HCl (10 mL). The aqueous
layer was extracted with methylene chloride (5.times.10 mL). The
combined organic layers were dried (MgSO.sub.4), filtered and
concentrated under vacuum to give
3-{4-[3-(biphenyl-4-yloxy)-propoxy]-3-trifluoromethoxy-phenyl}-2-methoxy--
propionic acid as a white solid (7 mg, 35%). .sup.1H-NMR
(CDCl.sub.3, 200.15 MHz): .delta. 7.57-7.32 (m, 9H), 7.00-6.95 (m,
3H), 4.27-4.19 (m, 4H), 3.97 (dd, 1H, J=7.3, 4.3), 3.41 (s, 3H),
3.16-2.93 (m, 2H), 2.31 (qn, 2H, J=5.8).
EXAMPLE 140
[1286]
(2S)-3-{6-[3-(Biphenyl-4-yloxy)-propoxy]-4'-methoxy-biphenyl-3-yl}--
2-methoxy-propionic acid 273
[1287] Step A
[1288] (4-Hydroxy-3-iodide)-2-methoxy dihidroinnamic acid 274
[1289] (4-Hydroxy)-2-methoxy dihydrocinnamic acid (1 g, 4.4 mmol)
was dissolved in 30 mL of CH.sub.3CN and cooled to -20.degree. C.
NIS was added (0.99 g, 4.43 mmol) and the mixture was stirred for 8
hours. The solvent was evaporated under vacuum and the crude oil
was washed with CCl.sub.4 with formation of a white solid. The
solid was removed by filtration, and the filtrate was concentrated
and purified by column chromatography (silica gel,
dichloromethane/MeOH 0.5%) Yellow oil (924 mg, 60%). .sup.1H-NMR
(200.15 MHz, CDCl.sub.3): .delta. 7.49 (d, 1H, J=2), 7.04 (dd, 1H,
J=2, 8.2), 6.80 (d, H, J=8.2), 6.03 (bs, 1H), 4.17 (q, 2H, J=7.2),
3.88 (dd, 1H, J=5.6, 7), 3.33 (s, 3H), 2.88 (dd, 2H, J=2.4, 5.0),
1.21 (t, 3H, J=7.2)
[1290] Step B
[1291]
(2S)-3-(6-Hydroxy-4)-methoxy-biphenyl-3-yl)-2-methoxy-propionic
acid 275
[1292] A solution of (2S)-(4-Hydroxy-3-iodide-)-2-methoxy
dihidrocinnamic acid (197 mg, 0.56 mmol), 4-methoxyphenyl boronic
acid (170.7 mg, 1.12 mmol) and
tetrakis(triphenylphosphine)-palladium (0) (8.7 mg, 0.5 mmol) in 11
mL of a mixture 20:1 toluene/ethanol together with 2 mL of a 2N
Na.sub.2CO.sub.3 was heated to 120.degree. for 16 hours under
nitrogen atmosphere. The reaction mixture was cooled to room
temperature and dilute with ethyl acetate (20 mL). It was washed
with H.sub.2O (3.times.5 mL) and brine (3.times.5 mL). The combined
organic layers were dried (MgSO.sub.4), filtered and concentrated
under vacuum. The resultant crude was purified by column
chromatography (silica gel, hexanes/ethyl acetate 8:2). Colorless
oil (123 mg, 67%). .sup.1H-NMR (200;15 MHz, CDCl.sub.3): .delta.
7.39 (dd, 2H, J=2.1, 6.4), 7.08-7.03 (m, 2H), 6.97 (dd, 2H, J=2.1,
6.7), 6.85 (dd, 1H, J=1.3, 7.5), 5.60 (s, 1H), 4.17 (q, 2H, J=7.0),
3.95 (dd, 1H, J=5.9, 6.4), 3.82 (s, 3H), 3.35 (s, 3H), 2.97 (d, 2H,
J=6.4), 1.22 (t, 3H, J=7.2)
[1293] Step C
[1294]
(2S)-3-{6-[3-(Biphenyl-4-yloxy)-propoxy]-4'-methoxy-biphenyl-3-yl}--
2-methoxy-propionic acid ethyl ester 276
[1295]
3-{6-[3-(Biphenyl-4-yloxy)-propoxy]4'-methoxy-biphenyl-3-yl}-2-meth-
oxy-propionic acid ethyl ester was prepared following the Standard
Procedure B (THF). The residue was purified by chromatography
(silica gel, hexanes/ethyl acetate 8:2). White solid (13 mg, 17%).
.sup.1H-NMR (200.15 MHz, CDCl.sub.3): 37.57 (m, 10H), 7.14 (dd, 2H,
J=2.1, 7.8), 6.94-6.87 (m, 4H), 4.24-4.04 (m, 6H), 3.94 (dd, 1H,
J=5.9, 6.9), 3.81 (s, 3H), 3.36 (s, 3H), 2.99 (d, 2H, J=6.9), 2.18
(qn, 2H, J=5.9), 1.22 (t, 3H, J=7.2).
[1296] Step D
[1297]
(2S)-3-{6-[3-(Biphenyl-4-yloxy)-propoxy]-4'-methoxy-biphenyl-3-yl}--
2-methoxy-propionic acid
[1298] The title compound was prepared following the procedure
described in example 25 (Step C). .sup.1H-NMR (200.15 MHz,
CDCl.sub.3): .delta. 7.57-6.87 (m, 16H), 4.15 (t, 2H, J=6.1), 4.07
(t, 2H, J=6.1), 4.01 (dd, 1H, J=7.2, 4.5), 3.80 (s, 3H), 3.41 (s,
3H), 3.13 (dd, 1H, J=4.5, 14.4), 2.99 (dd, 1H, J=7.1, 14.4), 2.21
(qn, 2H, J=5.9).
EXAMPLE 141
[1299] 3-{6-[3
{-(Biphenyl-4-yloxy)-propoxy]-4'-fluoro-biphenyl-3-yl]-2-me-
thoxy-propionic acid 277
[1300] The title compound was prepared as in Example 140, with
4-fluorophenyl boronic acid. .sup.1H-NMR (200.15 MHz, CDCl.sub.3):
.delta. 7.57-6.87 (m, 16H), 4.15 (t, 2H, J=5.9), 4.04 (t, 2H,
J=5.9), 4.02 (dd, 1H, J=7.2, 4.5), 3.41 (s, 3H), 3.13 (dd, 1H,
J=4.5, 14.2), 3.00 (dd, 1H, J=7.5, 14.2), 2.17 (qn, 2H, J=5.9).
EXAMPLE 142
[1301]
3-{6-[3-(Biphenyl-4-yloxy)-propoxy]-[1,1':4',1"]terphenyl-3-yl}-2-m-
ethoxy-propionic acid 278
[1302] The title compound was prepared as in Example 140, with
4-phenylphenyl boronic acid
EXAMPLE 143
[1303]
3-{6-[3-(Biphenyl-4-yloxy)-propoxy]-2'-methoxy-biphenyl-3-yl}-2-met-
hoxy-propionic acid 279
[1304] The title compound was prepared as in Example 140, with
2-methoxyphenyl boronic acid.
EXAMPLE 144
[1305]
2-Methoxy-3-{6-[3-(4-phenoxy-phenoxy)-propoxy]-[1,1':4',1"]terpheny-
l-3-yl}-propionic acid 280
[1306] The title compound was prepared as in Example 140, with
4-diphenyl boronic acid.
EXAMPLE 145
[1307]
3-{4-[3-(4-Benzoyl-phenoxy)-propoxy]-3-styryl-phenyl}-2-methoxy-pro-
pionic acid 281
[1308] The title compound was prepared as in Example 140, with
trans-2-phenylvinyl boronic acid
EXAMPLE 146
[1309]
3-(4-{3-[4-(Hydroxy-phenyl-methyl)-phenoxy]-propoxy}-3-phenethyl-ph-
enyl)-2-methoxy-propionic acid 282
[1310] A solution of
3-{4-[3-(4-Benzoyl-phenoxy)-propoxy]-3-styryl-phenyl}- -2-methoxy
propionic acid ethyl ester from Example 145, was dissolved in
ethanol and treated with H.sub.2 under balloon pressure. Filtered
through a pad of celite and concentrated to dryness. The compound
thus obtained was treated under standard hydrolysis procedure C to
give the title compound.
EXAMPLE 147
[1311]
3-{4-[3-(4-Benzyl-phenoxy)-propoxy]-3-phenethyl-phenyl}-2-methoxy-p-
ropionic acid 283
[1312] The title compound was obtained as a secondary product of
the reduction of
3-{4-[3-(4-Benzoyl-phenoxy)-propoxy]-3-styryl-phenyl}-2-meth-
oxy-propionic acid ethyl ester (from Example 145) as in Example
146, and was hydrolyzed under the standard hydrolysis procedure C
to afford the product.
EXAMPLE 148
[1313]
(2S)-3-{3-Allyl-4-[3-(4-phenoxy-phenoxy)-propoxy]-phenyl}-2-methoxy-
-propionic acid 284
[1314] Step A
[1315] (2S)-3-(3-Allyl-4-hydroxy-phenyl)-2-methoxy-propionic acid
ethyl ester 285
[1316] To a solution of 3-(4-hydroxy-phenyl)-2-methoxy-propionic
acid ethyl ester (1 eq) in acetone, K.sub.2CO.sub.3 (2 eq) and
alkyl bromide (1.2 eq) were added and the mixture reaction was
stirred at 55.degree. C. over night. Quenched with water and
extracted with ethyl acetate. The organic layer was dried
(MgSO.sub.4) and concentrated to give
3-(4-alkyloxy-phenyl)-2-methoxy-propionic acid ethyl ester. This
crude product was dissolved in Me.sub.2NPh and heated to reflux for
6 hours and then stirred at room temperature over 3 days. Refluxed
again for 8 hours and then poured into and ice-cold HCl 1M
solution, extracted with ethyl acetate and washed with water. Dried
and concentrated to give a crude product which was purified by
chromatography to give the title product.
[1317] Step B
[1318]
(2S)-3-{3-Allyl-4-[3-(4-phenoxy-phenoxy)-propoxy]-phenyl}-2-methoxy-
-propionic acid ethyl ester 286
[1319] (2S)-3-(3-Allyl-4-hydroxy-phenyl)-2-methoxy-propionic acid
ethyl ester from Step A was allowed to react with
4-(3-bromopropoxy)-1-phenoxyb- enzene under the Standard Procedure
I to give the title compound.
[1320] Step C
[1321]
(2S)-3-{3-Allyl-4-[3-(4-phenoxy-phenoxy)-propoxy]-phenyl}-2-methoxy-
-propionic acid
[1322]
(2S)-3-{3-Allyl-4-[3-(4-phenoxy-phenoxy)-propoxy]-phenyl}-2-methoxy-
-propionic acid ethyl ester from Step B was hydrolyzed under the
standard hydrolysis procedure C to afford the product.
EXAMPLE 149
[1323]
(2S)-2-Methoxy-3-{4-[3-(4-phenoxy-phenoxy)-propoxy]-3-propyl-phenyl-
}-propionic acid 287
[1324] A solution of
(2S)-3-{3-Allyl-4-[3-(4-phenoxy-phenoxy)-propoxy]-phe-
nyl}-2-methoxy-propionic acid ethyl ester, from Example 148, Step
B, was dissolved in ethanol and treated with H.sub.2 under balloon
pressure. Filtered through a pad of celite and concentrated to
dryness. The compound thus obtained was treated under, standard
hydrolysis procedure C to give the title compound.
EXAMPLE 150
[1325]
[3-{4-[3-(Biphenyl-4-yloxy)-propoxy]-2-methyl-phenyl}-2-methoxy-acr-
ylic acid 288
[1326] Step A
[1327] 4-Triisopropylsilanloxy-benzaldehyde 289
[1328] 4-hydroxybenzaldehyde (3 g, 24.57 mmol), triisopropylsilyl
chloride (5.52 mL, 25.79 mmol) and imidazol (2 g, 29.48 mmol) were
dissolved in 60 mL of DMF and the solution stirred at room
temperature overnight. Water (120 mL) was added to the solution and
the mixture extracted with diethyl ether (3.times.50 mL). The
combined extracts were washed with water (5.times.30 mL), saturated
ammonium chloride (2.times.30 mL) and brine (20 mL) and dried
(MgSO.sub.4). Concentration produced an oil that was purified by
chromatography (silica gel, hexanes/Ethyl acetate 20:1, R.sub.f0.4)
(75%). .sup.1H-NMR (CDCl.sub.3, 200.15 MHz): 9.85 (s, 1H), 7.75 (d,
2H, J=8.9), 6.95 (d, 2H, J=8.4), 1.31-1.20 (m, 3H), 1.10 (s,
18H).
[1329] Step B
[1330] 2-Methyl-4-triisopropylsilanyloxy-benzaldehyde 290
[1331] To a solution of trimethylethylenediamine (0.45 mL, 3.48
mmol) in THF (9 mL) at -20.degree. C. was added Butyllithium 1.6M
in hexanes (2.11 mL, 3.8 mmol). The solution was stirred at
-20.degree. C. for 15 min. A solution of
4-Triisopropylsilanyloxy-benzaldehyde (0.922 g, 3.31 mmol) was
added dropwise and the solution stirred for 15 min at -20.degree.
C. Bu 16M in hexanes (6.21 ml, 9.93 mmol) was added dropwise and
the solution kept in the freezer at -20.degree. C. for 26 hours.
The solution was cooled to 40.degree. C. and methyl iodide (3.71
mL, 59.60 mmol) was added. The solution was allowed to reach room
temperature and further stirred 30 ml. The reaction was quenched
with saturated ammonium chloride (20 mL) and extracted with ethyl
acetate (3.times.30 mL). The combined extracts were dried
(MgSO.sub.4), concentrated under vacuum and purified by column
chromatography (silica gel, hexanes/Ethyl acetate 20:1,
R.sub.f0.085) (49%). .sup.1H-NMR (CDCl.sub.3, 200.15 MHz): .delta.
10.1 (s, 1H), 7.69 (d, 1H, J=8.3), 6.80 (dd, 1H, J=8.6, 2.4), 6.72
(s, 1H), 0.61 (s, 3H), 1.33-1.19 (m, 3H), 1.12 (s, 18H).
[1332] Step C
[1333]
3-{4-[3-(Biphenyl-4-yloxy)-propoxy]-2-methyl-phenyl}-2-methoxy-acry-
lic acid methyl ester 291
[1334] Methyl 2-methoxyacetate (0.450 mL, 4.53 mmol) was added to a
solution of NaHDMS (4.74 mmol) in 40 mL of THF cooled to
-78.degree. C. The mixture was stirred at -78.degree. C. for 30 min
and then a solution of 2-Methyl-4-trisopropylsilanyloxybenzaldehyde
(1.26 g, 4.3 mmol) in 20 mL of THF was added dropwise. The solution
was allowed to warm to 0.degree. C. and stirred for 2.5 hours. The
mixture was quenched with HCl 1N (50 mL) at 0.degree. C., extracted
with dichloromethane (3.times.40 mL), dried (MgSO.sub.4) and
concentrated under vacuum. The residue was dissolved in
dichloromethane (50 mL) and cooled to 0.degree. C. To the solution
was added trifluoroacetic anhidride (0.82 mL, 5.84 mmol),
N,N-dimethylaminopyridine (0.025 g, 0.21 mmol), and pyridine (0.379
mL, 4.59 mmol). And stirred at room temperature for 4 hours. The
volatiles were eliminated under vacuum and the residue dissolved in
100 mL of ethyl acetate. Palladium 10% on activated carbon (0.9 g)
was added and the mixture hydrogenated at room temperature (5 Atm
H.sub.2) for 14 hours. The solution was filtered through a pad of
celite and concentrated under vacuum. The residue was purified by
column chromatography (silica gel, hexanes/Ethyl acetate 3:1) the
fractions with R.sub.f0.08 were collected and concentrated under
vacuum (0.249 g containing 3-(4-Hydroxy-2-methyl-p-
henyl)-2-methoxy-acrylic acid c.a. 85% pure by NMR). The residue
was added to a solution of 4-(3-Bromo-propoxy)-biphenyl (example
23, Step D) (0.359 g, 1.23 mmol), sodium iodide (0.05 g) and
potassium tert-butoxide (126 mg, 1.12 mmol) in 5 mL of
dimethylformamide. The solution was stirred at room temperature 24
hours, diluted with water and extracted with diethylether
(3.times.30 mL). The combined organic layers were washed with water
(5.times.30 ml), dried (MgSO.sub.4) and concentrated under vacuum.
The residue was purified by column chromatography (silica gel,
hexane:ethyl acetate 6:1, R.sub.f0.22). (0.18 mg, 10%). .sup.1H-NMR
(CDCl.sub.3, 200.15 MHz): .delta. 7.98 (d, 1H, J=8.6), 7.57-7.25
(m, 7H), 7.16 (s, 1H); 6.98 (dd, J=6.7, 2.1), 6.80-6.76 (m, 2H),
4.20 (t, 4H, J=5.9), 3.85 (s, 3H), 3.69 (s, 3H), 2.36 (s, 3H), 2.29
(t, 2H, J=6.2).
[1335] Step D
[1336]
3-{4-[3-(Biphenyl-4-yloxy)-propoxy]-2-methyl-phenyl}-2-methoxy-acry-
lic acid
[1337] The title compound was prepared from
3-(4-[3-(Biphenyl-4-yloxy)-pro-
poxy]-2-methyl-phenyl}-2-methoxy-acrylic acid methyl ester
following the general procedure B. .sup.1H-NMR (CDCl.sub.3, 200.15
MHz): 7.97 (d, 1H, J=8.4), 7.55-7.47 (m, 4H), 7.43-7.27 (m, 4H),
6.96 (dd, 2H, J=6.6, 2.2), 6.79-6.75 (m, 2H), 4.19 (t, 4H, J=6.2),
3.69 (s, 3H), 2.35 (s, 3H), 2.27 (t, 2H, J=6.2).
EXAMPLE 151
[1338]
3-{4-[3-(Biphenyl-4-yloxy)-propoxy]-2-methyl-phenyl}-2-methoxy-prop-
ionic acid 292
[1339] Step A
[1340]
3-{4-[3-(Biphenyl-4-yloxy)-propoxy]-2-methyl-phenyl}-2-methoxy-prop-
ionic acid methyl ester 293
[1341] Magnesium turnings (0.101 g, 4.17 mmol) was added to a
solution of
3-{4-[3-(Biphenyl-4-yloxy)-propoxy]-2-methyl-phenyl}-2-methoxy-acrylic
acid methyl ester (Example 37, Step C) (0.09 g, 0.21 mmol) in
methanol (2 mL) and diethyl ether (2 mL). The mixture was stirred
at room temperature overnight and then quenched with HCl 3N until
pH 7. A saturated solution of ammonium chloride (10 mL) was added
and the mixture extracted with ethyl ether (3.times.10 mL). The
combined extracts were dried (MgSO.sub.4) and concentrated under
vacuum. The residue was purified by column chromatography. (Silica
Gel, hexanes/Ethyl acetate 4.5:1, R.sub.f0.31) (48%). .sup.1H-NMR
(CDCl.sub.3, 200.15 MHz): 7.57-7.29 (m, 7H), 7.07 (d, 1H, J=8.1);
6.98 (dd, 2H, J=6.7, 2.1), 6.73 (s, 1H); 6.71 (d, 1H, J=11.8); 4.18
(dt, 4H, J=9.7, 6.2), 3.91 (dd, 1H, J=7.3, 6.2), 3.72 (s, 3H), 3.32
(s, 3H), 2.97 (d, 2H, J=6.4), 2.31 (s, 3H); 2.27 (t, 2H,
J=6.2).
[1342] Step B
[1343]
3-{4-[3-(Biphenyl-4-yloxy)-propoxy]-2-methyl-phenyl}-2-methoxy-prop-
ionic acid
[1344] The title compound was prepared from
3-{4-[3-(Biphenyl-4-yloxy)-pro-
poxy]-2-methyl-phenyl}-2-methoxy-propionic acid methyl ester
following the general procedure B. (71%). .sup.1H-NMR (CDCl.sub.3,
200.15 MHz): .delta. 7.55-7.27 (m, 7H); 7.09 (d, 1H, J=8.1); 6.96
(d, 2H, J=9.2); 6.71-6.67 (m, 2H); 4.15 (dt, 4H, J=9.1, 6.2); 3.92
(dd, 1H, J=8.4, 4.4); 3.31 (s, 3H); 3.08 (dd, 1H, J=14.6, 4.4);
2.93 (dd, 1H, J=14.3, 8.4); 2.30 (s, 3H); 2.25 (qn, 2H, J=6.2).
EXAMPLE 152
[1345]
3-{3-[3-(Biphenyl-4-yloxy)-propoxy]-phenyl}-2-methoxy-propionic
acid 294
[1346] Step A
[1347] 3-(3-Benzyloxy-phenyl)-3-hydroxy-2-methoxy-propionic acid
methyl ester 295
[1348] To a solution of NaHMDS (1.1 eq) in dry THF at -78.degree.
C. a mixture of 3-benzyloxy-benzaldehyde (1 eq) and methoxy-acetic
acid methyl ester (1.25 eq) in THF were added dropwise and the
mixture reaction at this temperature over 1.5 hours. Then the
reaction was quenched with HCl 3N and allowed to rise room
temperature. Washed with brine and extracted with ether. The
organic layer was dried and concentrated to dryness to, give after
chromatography in silica gel the title product.
[1349] Step B
[1350] 3-(3-Benzyloxy-phenyl)-2-methoxy-acrylic acid methyl ester
296
[1351] A mixture of
3-(3-Benzyloxy-phenyl)-3-hydroxy-2-methoxy-propionic acid methyl
ester (1 eq), mesylchloride (1 eq) triethylamine (4 eq) and a
catalytic amount of DMAP (0.1 eq) in dichloromethane was stirred at
room temperature overnight. The Reaction mixture was diluted with
ether and washed with HCl 1N. Dried and concentrated in vacuo to
give a residue which was chromatographed in silica gel to yield the
title compound.
[1352] Step C
[1353] 3-(3-Benzyloxy-phenyl)-2-methoxy-propionic acid methyl ester
297
[1354] Compound from Step B was dissolved in methanol and treated
with magnesium. The flask was placed in an ice bath for 5 min and
then the reaction mixture was stirred at room temperature for 4
hours. Washed with HCl 3N and extracted with ether. Dry and
concentrated to dryness to get the title compound.
[1355] Step D
[1356] 3-(3-Hydroxy-phenyl)-2-methoxy-propionic acid methyl ester
298
[1357] A solution of 3-(3-Benzyloxy-phenyl)-2-methoxy-propionic
acid methyl ester in methanol was treated with a catalytic amount
of C--Pd (0.1 eq) and then H.sub.2 was bubbled through the mixture
and stirred overnight. The mixture reaction was concentrated and
reconstituted in ethyl acetate, filtered through a pad of celite
and concentrated in vacuo to give the title compound.
[1358] Step E
[1359]
3-{3-[3-(Biphenyl-4-yloxy)-propoxy]-phenyl}-2-methoxy-propionic
acid
[1360] A mixture of 3-(3-Hydroxyphenyl)-2-methoxy-propionic acid
methyl ester (1 eq) from Step D, Cesium Carbonate (3 eq) and
4-(3-bromopropoxy)biphenyl (1 eq) in DMF and in a 10 mL tube was
shaked in an orbital agitator over a weekend. The mixture was
filtered through a hydrofobic syringer and evaporated in a
speed-vac apparatus. Then diluted with NaOH 1N-Ethanol and stirred
overnight. Then HCl 3N was added and the reaction mixture was
concentrated to remove the ethanol in vacuo, reconstituted in
dichloromethane and filtered through a hydrofobic syringe. The
organic layer was evaporated to give the title compound. MS (ES)
for C.sub.25H.sub.26O.sub.5 [M+NH.sup.4].sup.+: 424.2,
[M+Na].sup.+: 429.2. .sup.1H-NMR (CDCl.sub.3, 200.15 MHz):
7.57-7.17 (m, 9H), 6.98 (dd, 2H, J=6.7, 1.9), 6.84-6.81 (m, 3H),
4.19 (dd, 4H, J=14.0, 6.4), 4.03 (dd, 1H, J=7.3, 4.3), 3.40 (s,
3H), 3.13 (dd, 1H, J=14.2, 4.6), 2.98 (dd, 1H, J=14.0, 7.5), 2.28
(qui, 2H, J=5.9)ppm.
EXAMPLE 153
[1361]
'2-Methoxy-3-{3-[3-(4-phenoxy-phenoxy)-propoxy]-phenyl}-propionic
acid 299
[1362] The title compound was prepared from
3-(3-Hydroxy-phenyl)-2-methoxy- -propionic acid methyl ester from
Example 152, Step D with 4-(3-bromopropoxy)1-phenoxybenzene in a
manner analogous as in Example 152, Step E. MS (ES) for
C.sub.25H.sub.26O.sub.6 [M+NH.sub.4].sup.+: 440.2, [M+Na].sup.+:
445.2. .sup.1H-NMR (CDCl.sub.3, 200.15 MHz): 7.33-7.17 (m, 3H),
7.07-6.78 (m, 10H), 4.15 (dt, 4H, J=1.9, 6.2), 4.03 (dd, 1H, J=7.3,
4.3), 3.40 (s, 3H), 3.13 (dd, 1H, J=14.2, 4.6), 2.98 (dd, 1H,
J=14.0, 7.5), 2.25 (qui, 2H, J=5.9)ppm.
EXAMPLE 154
[1363]
3-{3-[3-Benzoyl-phenoxy)-propoxy]-phenyl}-2-methoxy-propionic acid
300
[1364] The title compound was prepared from
3-(3-Hydroxy-phenyl)-2-methoxy- -propionic acid methyl ester from
Example 152, Step D with
[4-(3-Bromo-propoxy)-phenyl]-phenyl-methanone in a manner analogous
as in Example 152, Step E. MS (ES) for C.sub.26H.sub.26O.sub.6
M+,].sup.+: 435.2, [M+Na].sup.+:457.2. .sup.1H-NMR (CDCl.sub.3,
200.15 MHz): 7.83-7.72 (m, 4H), 7.56-7.42 (m, 3H), 7.21 (dd, 2H,
J=9.1, 7.0), 6.97 (d, 2H, J=8.9), 6.82 (d, 1H, J=14.2), 6.82 (s,
2H), 4.25 (t, 2H, J=6.2), 4.16 (t, 2H, J=5.9), 4.02 (dd, 1H, J=7.5,
4.3), 3.40 (s, 3H), 3.12 (dd, 1H, J=14.0, 4.3), 2.98 (dd, 1H,
J=14.2, 7.5), 2.29 (qui, 2H, J=5.9).
EXAMPLE 155
[1365]
2-Methoxy-3-{3-[5-(4-phenoxy-phenoxy)-pent-1-ynyl]-phenyl}-propioni-
c acid 301
[1366] Step A
[1367] 2-Methoxy-3-(3-trifluoromethanesulfonyloxy-phenyl)-propionic
acid methyl ester 302
[1368] The title compound was prepared using the same procedure as
in Example 1, Step A starting from
3-(3-Hydroxy-phenyl)-2-methoxy-propionic acid methyl ester.
[1369] Step B
[1370] 3-[3-(5-Hydroxy-pent-1-ynyl)-phenyl]-2-methoxy-propionic
acid methyl ester 303
[1371] The title compound was prepared from 4-butyn-1-ol following
the procedure described, in Example 1, Step B.
[1372] Step C
[1373] 3-[3-(5-Bromo-pent-1-ynyl)-phenyl]-2-methoxy-propionic acid
methyl ester 304
[1374] To a solution of
3-[3-(5-Hydroxy-pent-1-ynyl)-phenyl]-2-methoxy-pro- pionic acid
methyl ester, and CBr.sub.4 dissolved in dichloromethane at
0.degree. C., triphenylphosphine was added and the mixture reaction
was stirred at room temperature over 5 hours.
[1375] The reaction then was diluted with water and extracted with
ether.
[1376] Chromatographied to give the title compound.
[1377] Step D
[1378]
2-Methoxy-3-{3-[5-(4-phenoxy-phenoxy)-pent-1-ynyl-3-phenyl]-propion-
ic acid methyl ester 305
[1379] A mixture of
3-[3-(5-Bromo-pent-1-ynyl)-phenyl]-2-methoxy-propionic acid methyl
ester (1 eq), 4-phenoxyphenol (1 eq) and Cesium carbonate (3 eq),
in DMF was stirred overnight. Then diluted in water and extracted
with ether to give after dry in vacuo the title compound.
[1380] Step E
[1381]
2-Methoxy-3-{3-[5-(4-phenoxy-phenoxy)-pent-1-ynyl]-phenyl}-propioni-
c acid
[1382] The title compound was prepared following the Standard
Hydrolysis Procedure C and starting from
2-Methoxy-3-{3-[5-(4-phenoxy-phenoxy)-pent--
1-ynyl]-phenyl}-propionic acid methyl ester from Step D. MS (ES)
for C.sub.27H.sub.26O.sub.5 [M+NH.sup.4].sup.+: 448.2,
[M+Na].sup.+:453.2. .sup.1H-NMR (CDCl.sub.3, 200.15 MHz): 7.33-7.17
(m, 7H), 7.07-6.88 (m, 7H), 4.11 (t, 2H, J=0.2), 4.00 (dd, 1H,
J=7.5, 4.0), 3.39 (s, 3H), 3.11 (dd, 1H, J=14.0, 4.3), 2.96 (dd,
1H, J=14.5, 7.8), 2.63 (t, 2H, J=7.0), 2.08 (qui, 2H, J=6.7).
EXAMPLE 156
[1383]
2-Methoxy-3-{3-[5-(4-phenoxy-phenoxy)-pentyl]-phenyl}-propionic
acid 306
[1384] The title compound was prepared from
2-Methoxy-3-{3-[5-(4-phenoxy-p-
henoxy)-pent-1-ynyl]-phenyl}-propionic acid of Example 155, Step E,
and treated with Pd (0.1 eq) in ethyl acetate and H.sub.2. Filtered
through celite and concentrated to give the compound. MS (ES) for
C.sub.27H.sub.36O.sub.5 [M+].sup.+: 435.2,
[M+NH.sub.4].sup.+:452.2. .sup.1H-NMR (CDCl.sub.3, 200.15 MHz):
7.34-7.19 (m, 3H), 7.09-6.84 (m, 10H), 4.02 (dd, 1H, J=7.5, 4.6),
3.94 (t, 2H, J=6.5), 3.39 (s, 3H), 3.13 (dd, 1H, J=14.0, 4.3), 3.00
(dd, 1H, J=14.0, 7.5), 2.63 (t, 2H, J=7.8), 1.88-1.45 (m,
6H)ppm.
EXAMPLE 157
[1385]
2-Methoxy-3-{3-[5-(4-phenoxy-phenoxy)-pentanoyl]-phenyl}-propionic
acid 307
[1386] The title compound was prepared from
2-Methoxy-3-{3-[5-(4-phenoxy-p-
henoxy)-pent-1-ynyl]-phenyl}-propionic acid methyl ester (Example
155, Step D) and following the same procedure as in Example 57, and
a standard hydrolysis procedure C to get the compound.
EXAMPLE 158
[1387]
3-{4-[3-(3-Allyl-biphenyl-4-yloxy)-propoxy]-phenyl}-2-methoxy-propi-
onic acid 308
[1388] Step A
[1389] 2-Allyl-4-phenoxy-phenol 309
[1390] To a solution of 4-phenylphenol (1 eq) in acetone,
K.sub.2CO.sub.3 (2-eq) and alkyl bromide (1.2 eq) were added and
the mixture reaction was stirred at 55.degree. C. overnight.
Quenched with water and extracted with ethyl acetate. The organic
layer was dried (MgSO.sub.4) and concentrated to give
4-allyloxybiphenyl. This crude product was dissolved in Me.sub.2NPh
and heated to reflux for 6 hours and then stirred at room
temperature over 3 days. Refluxed again for 8 hours and then poured
into and ice-cold HCl 1M solution, extracted with ethyl acetate and
washed with water. Dried and concentrated to give a crude product
which was purified by chromatography to give the title product.
[1391] Step B
[1392] 3-(3-Allyl-biphenyl-4-yloxy)-propan-1-ol 310
[1393] The product obtained in Step A (1.1 eq) was dissolved in THF
and treated with t-BuOK (1.15 eq) and allowed to react for 2 hours.
Then a solution of [1,3,2]Dioxathiolane 2,2-dioxide (1.0 eq) was
added and the mixture reaction was stirred overnight quenched with
HCl 6N and refluxed the reaction overnight. Extracted with ethyl
acetate, washed with brine and concentrated to give the title
compound.
[1394] Step C
[1395]
3-{4-[3-(3-Allyl-biphenyl-4-yloxy)-propoxy]-phenyl}-2-methoxy-propi-
onic acid ethyl ester 311
[1396] A solution of compound from Step B in dichloromethane was
treated with CBr.sub.4 (1.12 eq) and PPh.sub.3 (1.4 eq) and allow
to react for 1.5 hours. The product isolated after chromatography
of this reaction was treated under Standard Procedure I with
[1397] (2S)-3-(4-hydroxy-phenyl)-2-methoxy-propionic acid ethyl
ester to give the title compound.
[1398] Step D
[1399]
3-{4-[3-(3-Allyl-biphenyl-4-yloxy)-propoxy]-phenyl}-2-methoxy-propi-
onic acid
[1400] The title compound was prepared by using the standard
Hydrolysis Procedure (NaOH)C.
EXAMPLE 159
[1401]
(2S)-2-Methoxy-3-{4-[3-(3-propyl-biphenyl-4-yloxy)-propoxy]-phenyl}-
-propionic acid 312
[1402]
3-{4-[3-(3-Allyl-biphenyl-4-yloxy)-propoxy]-phenyl}-2-methoxy-propi-
onic acid from Example 158, Step D dissolved in ethyl acetate was
treated with Pd(C) 10% under balloon pressure for. 6 hours.
Filtered through celite and concentrated to dryness to give the
title compound.
EXAMPLE 160
[1403]
(2S)-3-{4-[3-(2-Allyl-4-phenoxy-phenoxy)-propoxy]-phenyl}-2-methoxy-
-propionic acid 313
[1404] Step A
[1405] 2-Allyl-4-phenoxyphenol 314
[1406] The title compound was prepared in a same manner as in
Example 158, Step A, starting from 4-phenoxyphenol.
[1407] Step B
[1408]
2-{4-[3-(2-Allyl-4-phenoxy-phenoxy)-propoxy]-phenyl}-3-methoxy-prop-
ionic acid ethyl ester 315
[1409] 3-[4-(3-Bromo-propoxy)-phenyl]-2-methoxy-propionic acid
ethyl ester and 2-Allyl-4-phenoxy-phenol from Step A were allowed
to react under Standard Procedure I to give the title compound.
[1410] Step C
[1411]
(2S)-3-{4-[3-(2-Allyl-4-phenoxy-phenoxy)-propoxy]-phenyl}-2-methoxy-
-propionic acid
[1412] The title compound was prepared by using the standard
Hydrolysis Procedure C (NaOH) to yield the compound.
EXAMPLE 161
[1413]
(2S)-2-Methoxy-3-{4-[3-(4-phenoxy-2-propyl-phenoxy)-propoxy]-phenyl-
}-propionic acid 316
[1414] The title compound was prepared from
2-{4-[4-(3-(2-Allyl-4-phenoxy--
phenoxy)-propoxy]-phenyl}-3-methoxy-propionic acid ethyl ester from
Example 160, Step B which was treated in ethyl acetate with Pd(C)
and H.sub.2 in balloon presure to give after filtration the
corresponding reduced product which was hydrolyzed under Standard
Procedure C to give the title compound.
EXAMPLE 162
[1415]
3-{4-[3-Biphenyl-4-yloxy)-propoxy]-3-methyl-phenyl}-2-methoxy-propi-
onic acid 317
[1416] Step A
[1417] 4-Benzyloxy-3-methyl-benzaldehyde 318
[1418] A mixture of benzyl bromide and
4-hydroxy-3-methylbenzaldehyde were treated under Standard
Procedure I to give the title product.
[1419] Step B
[1420]
3-(4-Benzyloxy-3-methyl-phenyl)-3-hydroxy-2-methoxy-propionic acid
ethyl ester 319
[1421] To a solution of NaHMDS (1.1 eq) in dry THF at -78.degree.
C. a mixture of 4-Benzyloxy-3-methyl-benzaldehyde (1 eq) and
Methoxy-acetic acid methyl ester (1.25 eq) in ID were added
dropwise and the mixture reaction at this temperature over 1.5
hours. Then the reaction was quenched with HCl 3N and allowed to
rise room temperature. Washed with brine and extracted with ether.
The organic layer was dried and concentrated to dryness to give
after chromatography in silica gel the title product.
[1422] Step C
[1423] 3-(4-Benzyloxy-3-methyl-phenyl-2-methoxy-acrylic acid ethyl
ester 320
[1424] A mixture of
3-(4-Benzyloxy-3-methyl-phenyl)-3-hydroxy-2-methoxy-pr- opionic
acid ethyl ester (1 eq), Mesylchloride (1 eq) triethylamine (4 eq)
and a catalytic amount of DMAP (0.1 eq) in dichloromethane was
stirred at room temperature over night. The reaction mixture was
diluted with ether and washed with HCl 1N. Dried and concentrated
in vacuo to give a residue which was chromatographed in silica gel
to yield the title compound.
[1425] Step D
[1426] 3-(4-Benzyloxy-3-methyl-phenol)-2-methoxy-propionic acid
ethyl ester 321
[1427] Compound from Step C was dissolved in methanol and treated
with magnesium.
[1428] The flask was placed in an ice bath for 5 min and then the
reaction mixture was stirred at room temperature for 4 hours.
Washed with HCl 3N and extracted with ether. Dry and concentrated
to dryness to get the title compound.
[1429] Step E
[1430] 3-(4-Hydroxy-3-methyl-phenyl)-2-methoxy-propionic acid ethyl
ester 322
[1431] A solution of
3-(4-Benzyloxy-3-methyl-phenyl)-2-methoxy-propionic acid ethyl
ester in ethyl acetate was treated with a catalytic amount of C--Pd
(0.1 eq) and then H.sub.2 was bubbled through the mixture and
stirred 2 hours. The mixture reaction was filtered through a pad of
celite and concentrated in vacuo to give the title compound.
[1432] Step F
[1433]
(2S)-3-{4-[3-(Biphenyl-4-yloxy)-propoxy]-3-methyl-phenyl}-2-methoxy-
-propionic acid ethyl ester 323
[1434] A mixture of
3-(4-Hydroxy-3-methyl-phenyl)-2-methoxy-propionic acid ethyl ester
and from Step E and 4-(3-bromopropoxy)biphenyl were treated under
standard condition I to give the title product.
[1435] Step G
[1436]
3-{4-[3-(Biphenyl-4-yloxy)-propoxy]-3-methyl-phenyl}-2-methoxy-prop-
ionic acid
[1437] The title compound was prepared from compound from Step F
under Standard hydrolysis procedure C using NaOH.
EXAMPLE 163
[1438]
2-Methoxy-3-{3-methyl-4-[3-(4-phenoxy-phenoxy)-propoxy]-phenyl}-pro-
pionic acid 324
[1439] Step A
[1440]
2-Methoxy-3-{3-methyl-4-[3-(4-phenoxy-phenoxy)-propoxy]-phenyl}-pro-
pionic acid ethyl ester 325
[1441] A mixture of 3-(Hydroxy-3-methyl-phenyl)-o-methoxy-propionic
acid ethyl ester and from Example 162, Step E and
4-(3-bromopropoxy)-phenoxyph- enyl were treated under standard
condition I to give the title product.
[1442] Step B
[1443] The title compound was prepared from compound from Step A
under Standard hydrolysis procedure C using NaOH.
EXAMPLE 164
[1444]
3-{4-[3-(4-Benzoyl-phenoxy)-propoxy]-3-methyl-phenyl}-2-methoxy-pro-
pionic acid 326
[1445] Step A
[1446]
3-[4-(3-Benzoyl-phenoxy)-propoxy]-3-methyl-phenyl}-2-methoxy-propio-
nic acid ethyl ester 327
[1447] A mixture of
3-(4-Hydroxy-3-methyl-phenyl)-2-methoxy-propionic acid ethyl ester
and from Example 162, Step B and [4-(3-Bromo-propoxy)-phenyl]-
-phenyl-methanone were treated under standard condition I to give
the title product.
[1448] Step B
[1449]
3-{4-[3-(4-Benzoyl-2-phenoxy)-propoxy]-3-methyl-phenyl}-2-methoxy-p-
ropionic acid
[1450] The title compound was prepared from compound from Step A
under Standard hydrolysis procedure C using NaOH.
EXAMPLE 165
[1451]
(2S)-3-[4-(3-(Dibenzofuran-2-yloxy)-propoxy]-phenyl}-2-methoxy-prop-
ionic acid 328
[1452] Step A
[1453] 3-(Dibenzofuran-2-yloxy-propan-1-ol 329
[1454] A solution of 2-hydroxydibenzofurane, potassium
tert-butoxide and [1,2,3]dioxathiane-2,2-dioxide were treated as
the same manner as in Example 132, Step C, to give the title
product.
[1455] Step B
[1456] 2-(3-Bromo-propoxy)-dibenzofuran 330
[1457] Starting from compound of Step A and following the procedure
described in Example 132, Step D we obtained the title
compound.
[1458] Step C
[1459]
3-{4-[3-(Dibenzofuran-2-yloxy)-propoxy]-phenyl}-2-methoxy-propionic
acid ethyl ester 331
[1460] A mixture of 2-(3-Bromo-propoxy)-dibenzofuran and
(2S)-3-(4-hydroxy-phenyl)-2-methoxy propionic acid ethyl ester were
allowed to react under the Standard Procedure I to give the title
compound.
[1461] Step D
[1462]
(2S)-3-{4-[3-(Dibenzofuran-2-yloxy)-propoxy]-phenyl}-2-methoxy-prop-
ionic acid
[1463] The title compound was prepared from Step C using the
standard hydrolysis procedure C (NaOH).
EXAMPLE 166
[1464]
(2S)-3-[4-3-{4-[(4-Fluoro-phenyl)-hydroxyimino-methyl]-phenoxy}-pro-
poxy)-phenyl]-2-methoxy-propionic acid 332
[1465] The title compound was prepared from
(2S)-3-(4-{3-[4-(4-Fluoro-benz-
oyl)-phenoxy]-propoxy}-phenyl)-2-methoxy-propionic acid (Example
95), and was treated under the same conditions as in Example 61, to
give the title compound.
EXAMPLE 167
[1466]
(2S)-3-[4-(3-{4-[(4-Fluoro-phenyl)-hydroxy-methyl]-phenoxy}-propoxy-
)-phenyl]-2-methoxy-propionic acid 333
[1467] Step A
[1468]
(2S)-3-[4-(3-{4-[(4-Fluor-phenyl)-hydroxy-methyl]-phenoxy}-propoxy)-
-phenyl]-2-methoxy-propionic acid ethyl ester 334
[1469] The title compound was prepared from
(2S)-3-(4-{3-[4-(4-Fluoro-benz-
oyl)-phenoxy]-propoxy}-phenyl)-2-methoxy-propionic acid ethyl ester
(Example 95) which was dissolved in methanol and treated at
0.degree. C. with NaBH.sub.4 (2 eq) for 6 hours. Washed with water
and extracted with dichloromethane to give after purification by
chromatography the title compound.
[1470] Step B
[1471]
(2S)-3-[4-(3-{4-[(4-Fluoro-phenyl)-hydroxy-methyl]-phenoxy}-propoxy-
)-phenyl]-2-methoxy-propionic acid
[1472] The title compound was prepared from Step A by standard
hydrolysis procedure C (NaOH).
EXAMPLE 168
[1473]
(2S)-2-Methoxy-3-(4-{3-[4-(4-piperidin-1-benzoyl]-propoxy}-phenyl)--
propionic acid 335
[1474] Step A
[1475]
(2S)-2-Methoxy-3-(4-{3-[4-(4-piperidin-1-yl-benzoyl)-phenoxy]-propo-
xy}-phenyl)-propionic acid ethyl ester 336
[1476] To a solution of
(2S)-3-(4-{3-[4-(4-Fluoro-benzoyl)-phenoxy]-propox-
y}-phenyl)-2-methoxy-propionic acid ethyl ester (Example 95) in
DMSO, piperydine (3 eq) was added and the mixture reaction was
heated to 140.degree. C. for 2 days. The reaction was extracted
with ethyl acetate and washed (several times) with water.
Concentrated to dryness and chromatographied to give the title
compound.
[1477] Step B
[1478]
(2S)-2-Methoxy-3-(4-{3-[4-(4-piperidin-1-yl-benzoyl)-phenoxy]-propo-
xy}-phenyl)-propionic acid
[1479] The title compound was prepared from Step A by standard
hydrolysis procedure C (LiOH). MS (ES) for C.sub.3H.sub.35NO.sub.6
[M+H].sup.+: 518.
EXAMPLE 169
[1480]
(2S)-2-Methoxy-3-(4-{3-[4-(4-morpholin-4-yl-benzoyl)-phenoxy]-propo-
xy}-phenyl)-propionic acid 337
[1481] Step A
[1482]
(2S)-2-Methoxy-3-(4-{3-[4-(4-morpholin-4-yl-benzoyl)-phenoxy-propox-
y}-phenyl)-propionic acid ethyl ester 338
[1483] To a solution of
(2S)-3-(4-{3-[4-(4-Fluoro-benzoyl)-phenoxy]-propox-
y}-phenyl)-2-methoxy-propionic acid ethyl ester (Example 95) in
DMSO, morpholyne (3 eq) was added and the mixture reaction was
heated to 140.degree. C. for 2 days. The reaction was extracted
with ethyl acetate and washed (several times) with water.
Concentrated to dryness and chromatographed to give the title
compound.
[1484] Step B
[1485]
(2S)-2-Methoxy-3-(4-{3-[4-(4-morpholin-4-benzoyl)-phenoxy]-propoxy}-
-phenyl)-propionic acid
[1486] The title compound was prepared from Step A by standard
hydrolysis procedure C (LiOH). MS (ES) for C.sub.30H.sub.33NO.sub.7
[M+H].sup.+: 520.
EXAMPLE 170
[1487]
(2S)-3-(4-{3-[4-(4-Hydroxy-benzoyl)-phenoxy]-propoxy}-phenyl)-2-met-
hoxy-propionic acid 339
[1488] A solution of
(2S)-3-(4-{3-[4-(4-Fluoro-benzoyl)-phenoxy]-propoxy}--
phenyl)-2-methoxy-propionic acid (85 mg) (Example 95) and KOH (100
mg) in chlorobenzene (0.3 ml) with water (1 ml) were heated in
sealed tube at 200.degree. C. for 3 days. Extracted with ethyl
acetate, dried and concentrated to dryness to give a crude product
which was purified by chromatography to give the title compound. MS
(ES) for C.sub.26H.sub.26O.sub.7 [M+H].sup.+: 451.
EXAMPLE 171
[1489]
(2S)-2-methoxy-3-{4-[3-(4-phenoxy-phenoxy)-propoxy]phenyl}propanoic
acid sodium salt 340
[1490] Step 1: 1-chloro-3-(4-phenoxyphenyl propane (a) 341
[1491] The compound of 4-phenoxyphenol (81.03 g, 435.5 mmol) was
dissolved in 810 ml MEK at ambient temperature under Nitrogen.
Powdered potassium carbonate (577.16 g, 4,176.27 mmol) was added
followed by 1,3-dichloropropane (300.00 g, 2,655.1 mmol), and the
resulting solution was heated to reflux for 15.5 hours. The
solution was cooled to room temperature, filtered and washed with
750 ml MEK. The filtrate was concentrated under vacuum to give a
crude orange liquid. The crude liquid was dissolved in 260 ml
absolute MeOH at ambient temperature and stirred 5 minutes, which
was then cooled in an ice/acetone/water bath for 1.5 hours.
[1492] White precipitate was filtered off and washed with 480 ml
cold absolute MeOH. The white solid was collected and dried under
vacuum at 30.degree. C. for 16 hours to afford about 81.87 g of
compound (a).
[1493] Step 2:
2S-2-methoxy-3-{4-[3-(4-phenoxy-phenoxy)-propoxy]-phenyl}-p-
ropanoic acid sodium salt 342
[1494] The compound (b) (10.9 g, 50 mmol) was dissolved in 50 ml
absolute ethanol at ambient temperature. Sodium methoxide (4.05 g,
75 mmol) was added all at once, and the resulting solution was
heated to reflux for 30 minutes. The solution was cooled to
40.degree. C. and the compound (a) (15.72 g, 75 mmol) was added all
at once followed by 50 ml DMF and 50 ml DMSO. The clear red
solution was heated to reflux for 30 minutes, and cooled to ambient
temperature. The ethanol was removed under vacuum at 60.degree. C.,
and a mixture 100 ml of water and 100 ml MTBE was added. The top
organic layer was separated and discarded Fresh MTBE (100 ml) was
added and crystallization occurred. The biphasic slurry was stirred
at ambient temperature for 30 minutes, filtered and washed with 250
ml MTBE. The white solid was dried under vacuum at 60.degree. C.
for 16 hours to afford about 15.34 g of the title compound.
EXAMPLE 172
[1495]
(2S)-3-[4-(3-{4-[Hydroxyamino-(4-hydroxy-phenyl)-methyl]-phenoxy}-p-
ropoxy)-phenyl]-2-methoxy-prop ionic acid 343
[1496] The title compound was prepared from
(2S)-3-(4-{3-[4-(4-Hydroxy-ben-
zoyl)-phenoxy]-propoxy}-phenyl)-2-methoxy-propionic acid (Example
170), and was treated under the same conditions as in Example 61,
to give the title compound. MS (ES) for C.sub.26H.sub.27NO.sub.7
[M-H].sup.-: 464.
EXAMPLE 173
[1497]
(2S)-3-{4-[3-(4-Benzoyl-3-hydroxy-phenoxy)-propoxy]-phenyl}-2-metho-
xy-propionic acid 344
[1498] Step A
[1499] (2S)-3-[4-(3-Bromo-propoxy)-phenyl]-2-methoxy-propionic acid
ethyl ester 345
[1500] The title compound was prepared from
(2S)-3-[4-(3-Hydroxy-propoxy)-- phenyl]-2-methoxy-propionic acid
ethyl ester from Example 171, Step B, and following the procedure
described in Example 132, Step D we obtained the title
compound.
[1501] Step B
[1502]
3-{4-[3-(4-Benzoyl-3-hydroxy-phenoxy)-propoxy]-phenyl}-2-methoxy-pr-
opionic acid ethyl ester 346
[1503] A mixture of
(2S)-3-[4-(3-Bromo-propoxy)-phenyl]-2-methoxy-propioni- c acid
ethyl ester from Step A and 2,4-dihydroxybenzophenone were allowed
to react under the Standard Procedure I to get to title
compound.
[1504] Step C
[1505]
(2S)-3-{4-[3-(4-Benzoyl-3-hydroxy-phenoxy)-propoxy]-phenyl}-2-metho-
xy-propionic acid
[1506] The title compound was prepared from Step B by standard
hydrolysis procedure C (LiOH). MS (ES) for C.sub.26H.sub.26O.sub.7
[M-H].sup.-: 449.
EXAMPLE 174
[1507]
(2S)-3-(4-{3-[4-(2,4-Dimethoxy-benzoyl)-phenoxy]-propoxy}-phenyl)-2-
-methoxy-propionic acid 347
[1508] Step A
[1509]
3-(4-{3-[4-(2,4-Dimethoxy-benzoyl)-phenoxy]-propoxy}-phenyl)-2-meth-
oxy-propionic acid ethyl ester 348
[1510] A mixture of
(2S)-3-[4-(3-Bromo-propoxy)-phenyl]-2-methoxy-propioni- c acid
ethyl ester from 0, Step A and 2,4-dimethoxy-4'hydroxybenzophenone
were allowed to react under the Standard Procedure I to get to
title compound.
[1511] Step B
[1512]
(2S)-3-(4-{3-[4-(2,4-Dimethoxy-benzoyl)-phenoxy]-propoxy}-phenyl)-2-
-methoxy-propionic acid
[1513] The title compound was prepared from Step A by standard
hydrolysis procedure C (LiOH). MS (ES) for C.sub.28H.sub.30O.sub.8
[M-H].sup.-: 493.
EXAMPLE 175
[1514]
3-{4-[3-(4-Benzyl-phenoxy-propoxy]-3-methoxy-phenyl}-2-methoxy-prop-
ionic acid 349
[1515] Step A
[1516]
3-[4-(3-Hydroxy-propoxy)-3-methoxy-phenyl]-2-methoxy-propionic acid
350
[1517] A mixture of
3-(4-Hydroxy-3-methoxy-phenyl)-2-methoxy-propionic acid ethyl ester
(Example 130, Step A) and 3-(tert-Butyl-dimethyl-silanyl-
oxy)-propan-1-ol were treated under Mitsounobu coupling standard
conditions B using DIAD and toluene. The product thus obtained was
treated under Standard Procedure E for cleaveage protected alcohols
to give the title product.
[1518] Step B
[1519]
3-{4-[3-Bromo-propoxy)-3-methoxy]-phenyl}-2-methoxy-propionic acid
351
[1520] The title compound was prepared from
3-[4-(3-Hydroxy-propoxy)-3-met- hoxy-phenyl]-2-methoxy-propionic
acid and following the procedure described in Example 132, Step D
we obtained the title compound.
[1521] Step C
[1522]
3-{4-[3-(4-Benzyl-phenoxy)-propoxy]-3-methoxy-phenyl}-2-methoxy-pro-
pionic acid
[1523] The title compound was prepared from
3-[4-(3-Bromo-propoxy)-3-metho- xy-phenyl]-2-methoxy-propionic acid
and 4-benzylphenol following the Standard Procedure J. MS (ES) for
C.sub.27H.sub.30O.sub.6 [M+NH.sub.4].sup.+: 468, [M+Na].sup.+:
473.
EXAMPLE 176
[1524] (S)-3-(4-benzyloxy-phenyl)-2-isopropoxy-propionic acid
352
[1525] Step 1: A solution containing
(S)-5-(4-benzyloxy-benzyl)-2,2-dimeth- yl-[1,3]dioxolan-4-one
(S)-3-(4-benzyloxy-phenyl)-2-hydroxy-propionic acid (2.0 g, 7.34
mmol), 2,2-dimethoxypropane (18.63 g, 0.179 mol) and pyrididium
p-toluene sulfonate (0.92 g, 3.66 mmol) in chloroform (80 mL) was
heated to reflux for 40 minutes under N.sub.2. The reaction was
cooled, diluted with water and extracted with CH.sub.2Cl.sub.2. The
organic layer was dried (Na.sub.2SO.sub.4) and the solvent was
removed in vacuo to give crude product which was purified by a
flash chromatography using 10:1 hexanes:acetone to afford about
2.01 g (88%) of
(S)-5-(4-benzyloxy-benzyl)-2,2-dimethyl-[1,3]dioxolan-4-one.
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.43-7.29 (m, 5H), 7.17
(d, 2H, J=8.80 Hz), 6.91 (d, 2H, J=8.80 Hz), 5.04 (s, 2H), 4.61
(dd, 1H, J=6.36 Hz, J=4.40 Hz), 3.12 (dd, 1H, J=14.67 Hz, J=4.40
Hz), 2.99 (dd, 1H, J=14.67 Hz, J=6.36 Hz), 1.49 (s, 3H), 1.36 (s,
3H). MS (ES.sup.+) m/z exact mass calculated for
C.sub.19H.sub.20O.sub.4 (M+NH.sub.4) 330. Found m/z 330.
[1526] Step 2: (S)-3-(4-benzyloxy-phenyl)-2-isopropoxy-propionic
acid
[1527] A -78.degree. C. solution of
(S)-5-(4-benzyloxy-benzyl)-2,2-dimethy- l-[1,3]dioxolan-4-one (0.20
g, 0.64 mmol) and triethylsilane (0.223 g, 1.92 mmol) in
CH.sub.2Cl.sub.2 (8 mL) was treated dropwise with a 1 molar
solution of TiCl.sub.4 in CH.sub.2Cl.sub.2 (0.64 mL, 0.64 mmol)
under N.sub.2. The solution was stirred at -78.degree. C. for 15
minutes and then quenched with water. The mixture was extracted
with EtOAc, and the organic layer was dried (Na.sub.2SO.sub.2). The
organic layer was filtered, and the solvent was removed in vacuo to
give crude product which was purified by a flash chromatography
using 5:1 hexanes:acetone to afford 0.171 g (85%)
(S)-3-(4-benzyloxy-phenyl)-2-isopropoxy-propionic acid. .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. 12.50 (bs, 1H), 7.42-7.27 (m, 5H),
7.12 (d, 2H, J=8.80 Hz), 6.88 (d, 2H, J=8.80 Hz), 5.02 (s, 2H),
3.96 (dd, 1H, J=7.83 Hz, J=4.89 Hz), 3.47 (hp, 1H, J=5.87 Hz), 2.83
(dd, 1H, J=13.69 Hz, J=4.89 Hz), 2.71 (dd, 1H, J=13.69 Hz, J=8.31
Hz), 1.02 (d, 2H, J=5.87 Hz), 0.86 (d, 2H, J=5.87 Hz). IR (KBr)
3012, 2977, 2931, 1767, 1722, 1610, 1511, 1380, 1240, 1116, 1020.
HRMS (TOF ES.sup.-) m/z exact mass calculated for
C.sub.19H.sub.21O.sub.4 (M-1) 13.1440. Found m/z 313.1434.
EXAMPLE 176A
[1528]
(2S)-2-isopropoxy-3-{4-[3-(4-phenoxy)-phenoxy)-propoxy]phenyl}propa-
noic acid sodium salt 353 354
[1529] (S)-3-(4-hydroxy-phenyl)-2-methoxy-propionic-acid ethyl
ester 355
[1530] A solution of (S)-3-(4-hydroxy-phenyl)-2-methoxy-propionic
acid (20 g, 100 mmol) in 3 A ethanol (140 mL) was treated dropwise
with concentrated sulfuric acid (5.7 mL)) and stirred at room
temperature overnight. The solution was concentrated and is water
(110 mL) was added. Sodium bicarbonate was added to bring the pH to
7-8. The mixture was extracted with ethyl acetate (3.times.50 mL).
The combined organic layers were washed with 20% NaCl solution (50
ml), dried (MgSO.sub.4), filtered, and concentrated to a golden oil
(18 g, 80%). .sup.1H-NMR (CDCl.sub.3): 7.1 (d, 2H); 6.7 (d, 2H);
4.2 (m, 2H); 3.9 (m, 1H); 3.6 (s, 3H); 2.95 (m, 2H); 125 (t, 3H).
MS (ES): 223.2 (M-1).
[1531] (S)-3-(4-benzyloxy-phenyl)-2-hydroxy-propionic acid 356
[1532] (S)-2-Hydroxy-3-(4-hydroxy-phenyl)-propionic acid (121 g,
0.664 mol) (Wang et al. Tetrahedron Lett. 1998, 39, 5501) in
absolute EtOH (2 L) was treated with potassium carbonate (184 g,
1.33 mol) and benzyl chloride 169 g, 1.34 mol). The mixture was
heated at reflux overnight and concentrated to about half the
volume under vacuum. Aqueous 5N NaOH (100 mL) was added, and the
mixture was stirred at ambient temperature overnight and then
concentrated. The residue was acidified with concentrated HCl. The
yellow sold was collected by filtration and dried overnight under
vacuum at 50.degree. C. The crude product in isopropanol (1.8 L)
was heated at reflux for about 30 minutes, cooled to ambient
temperature, and stirred for about 16 hours. The slurry was
filtered and dried under vacuum at 70.degree. C. overnight to give
the title compound as a white solid (137 g, 76%).
[1533] Step A:
(S)-5-(4-benzyloxy-benzyl)-2,2-dimethyl-[1,3]dioxolan-4-one
[1534] (S)-3-(4-Benzyloxy-phenyl)-2-hydroxy-propionic acid (2.0 g,
7.34 mmol), 2,2-dimethoxypropane (18.63 g, 0.179 mol) and
pyridinium p-toluene sulfonate (0.92 g, 3.66 mmol) in chloroform
(80 mL) was heated to reflux for 40 minutes under N.sub.2. The
mixture was cooled, diluted with water, and extracted with
CH.sub.2Cl.sub.2. The organic layer was dried (Na.sub.2SO.sub.4)
and concentrated in vacuo to give crude product that was purified
by flash chromatography using 10:1 hexanes:acetone to afford the
title compound (2.01 g, 88%). .sup.1H-NMR (400 MHz, CDCl.sub.3)
.delta. 7.43-7.29 (m, 5H), 7.17 (d, 2H, J=8.80 Hz), 6.91 (d, 2H,
J=8.80 Hz), 5.04 (s, 2H), 4.61 (dd, 1H, J=6.36 Hz, J=4.40 Hz), 3.12
(dd, 1H, J=14.617 Hz, J=4.40 Hz), 2.99 (dd, 1H, J=14.67 Hz, J=6.36
Hz), 1.49 (s, 3H), 1.36 (s, 3H). MS (ES.sup.+) m/z calc'd for
C.sub.19H.sub.20O.sub.4 (M+NH.sub.4) 330. Found m/z 330.
[1535] Step B: (S)-5-(4-hydroxy-benzyl)-2,2-dimethyl-[1,3]dioxolane
one
[1536] (S)-5-(4-benzyloxy-benzyl)-2,2-dimethyl-[1,3]dioxolan-4-one
(1.0 g, 3.2 mmol) was combined with 10% Pd/C (0.75 g) in EtOAc (40
mL) and purged with N.sub.2 then H.sub.2 and then stirred under a
hydrogen balloon for 3 hours. Sodium sulfate was added, and the
mixture was filtered through Celite. The solvent was removed in
vacuo to afford the title compound (0.747 g, 100%). .sup.1H NMR
(400 MHz, CDCl.sub.3) .delta. 7.11 (d, 2H, J=8.31 Hz), 6.76 (d, 2H,
J=8.31 Hz), 4.93 (bs, 1H), 4.61 (dd, 1H, J=6.36 Hz, J=0.440 Hz),
3.11 (dd, 1H, J=14.67 Hz, J=4.40 Hz), 2.98 (dd, 1H, J=14.67 Hz,
J=5.86 Hz), 1.49 (s, 3H), 1.36 (s, 3H). MS (ES) m/z mass calc'd for
C.sub.12H.sub.14O.sub.4 (M-1) 221, Found m/z 221.
[1537] Step C: (S)-3-(4-hydroxy-phenyl)-2-isopropoxy-propionic acid
ethyl ester
[1538] A 0.degree. C. solution of
(S)-5-(4-hydroxy-benzyl)-2,2-methyl-[1,3- ]dioxolan-4-one (0.20 g,
0.90 mmol) and triethylsilane (1.05 g, 9.02 mmol) in
CH.sub.2Cl.sub.2 (10 mL) was treated dropwise with TiCl.sub.4 (0.90
mL, 0.90 mmol, 1M CH.sub.2Cl.sub.2) under N.sub.2. The solution was
stirred at 0.degree. C. for about 15 min and warmed to room
temperature. After about 45 minutes, the mixture was quenched with
water and extracted with EtOAc. The organic layer was dried
(Na.sub.2SO.sub.2), filtered, and concentrated in vacuo to give of
crude product (0.32 g). This material was combined with ethanol (25
mL) and conc. H.sub.2SO.sub.2 (1 mL) and stirred for 17 hours at
room temperature under N.sub.2. The mixture was concentrated and
partitioned between EtOAc and water. The organic layer was dried
(Na.sub.2SO.sub.2), filtered, and concentrated in vacuo. The crude
product was purified by flash chromatography using 5:1
hexanes:acetone to afford the title compound (0.158 g, 70%).
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.11 (d, 2H, J=8.31 Hz),
6.76 (d, 2H, J=8.31 Hz), 4.79 (bs, 1H), 4.20-4.12 (m, 2H), 3.99
(dd, 1H, J=8.56 Hz, J=4.89 Hz), 3.49 (hp, 1H, J=6.36 Hz), 2.94-2.83
(m, 2H), 1.23 (t, 3H, J=6.85 Hz), 1.14 (d, 3H, J=6.36 Hz), 0.96 (d,
3H, J=6.36 Hz). MS (ES) m/z calc'd for C.sub.14H.sub.20O.sub.4
(M-1) 251. Found m/z 251.
[1539] Step D:
(S)-2-isopropoxy-3-{4-[3-(4-phenoxy-phenoxy)-propoxy]-pheny-
l}-propionic acid
[1540] The synthesis of
(2S)-2-isopropoxy-3-{4-3-(4-phenoxy-phenoxy)-propo-
xy]phenyl}propanoic acid sodium salt was completed according to
procedures described in Example 171. .sup.1H NMR (400 MHz,
CDCl.sub.3): .delta. 0.96 (d, 3H, J=5.9 Hz), 1.09 (d, 3H, J=6.3
Hz), 2.22 (quartet, 2H, J=5.9 Hz), 2.82 (dd, 1H, J=9.3 Hz, 13.7
Hz), 3.01 (dd, 1H, J=2.5 Hz, 13.7 Hz), 3.43 (q, 1H, J=5.9 Hz), 4.01
(dd, 1H, J=3.4, 8.8 Hz), 4.11 (q, 4H, J=6.4 Hz), 6.80 (d, 2H, J=8.3
Hz), 6.88 (d, 2H, J=8.8 Hz), 6.90-7.00 (m, 4H), 7.01-7.05 (m, 1H),
7.17 (d, 2H, J=8.3 Hz), 7.28 (d, 2H, J=8.8 Hz). MS: 451.2 (I).
EXAMPLE 177
[1541]
2-Methoxy-3-{3-methoxy-4-[3-(4-phenylacetyl-phenoxy)-propoxy]-pheny-
l}-propionic acid 357
[1542] The title compound was prepared from
3-[4-(3-Bromo-propoxy)-3-metho- xy-phenyl]-2-methoxy-propionic acid
(Example 175, Step B) and 1-(4-Hydroxy-phenyl)-2-phenyl-ethanone
following the Standard Procedure J. MS (ES) for
C.sub.28H.sub.30O.sub.7 [M+H].sup.+: 479.
EXAMPLE 178
[1543]
3-{4-[3-(4-Butoxy-phenoxy)-propoxy]-3-methoxy-phenyl}-2-methoxy-pro-
pionic acid 358
[1544] The title compound was prepared from
3-[4-(3-Bromo-propoxy)-3-metho- xy-phenyl]-2-methoxy-propionic acid
(Example 175, Step B) and 4-Butoxy-phenol following the Standard
Procedure J. MS (ES) for C.sub.24H.sub.32O.sub.7 [M+Na].sup.+:
455.
EXAMPLE 179
[1545]
2-Methoxy-3-{3-methoxy-4-[3-(4-oxo-2-phenyl-4H-chromen-6-yloxy)-pro-
poxy]-phenyl}-propionic acid 359
[1546] The title compound was prepared from
3-[4-(3-Bromo-propoxy)-3-metho- xy-phenyl]-2-methoxy-propionic acid
(Example 175, Step B) and 6-Hydroxy-2-phenyl-chromen-4-one
following the Standard Procedure J. .sup.1H-NMR (200.15 MHz,
CDCl.sub.3): 8.0-7.9 (m, 2H), 7.6-7.5 (m, 5H), 7.30 (dd, 1H, J=9.0,
3.0), 6.9-6.8 (m, 4H), 4.34.2 (m, 4H), 4.00 (dd, 1H, J=7.2, 4.6),
3.83 (s, 3H), 3.41 (s, 3H), 3.09 (dd, 1H, J=14.2, 4.6), 22.96 (dd,
1H, J=14.2, 7.2), 2.33 (qn, 2H, J=6.2) ppm.
EXAMPLE 180
[1547]
2-Methoxy-3-(3-methoxy-4-{3-[4-(4-trifluoromethyl-phenoxy)-phenoxy]-
-propoxy}-phenyl)-propionic acid 360
[1548] The title compound was prepared from
3-[4-(3-Bromo-propoxy)-3-metho- xy-phenyl]-2-methoxy-propionic acid
(Example 175, Step B) and 4-(4-Trifluoromethyl-phenoxy)-phenol
following the Standard Procedure J. MS (ES) for
C.sub.27H.sub.27F.sub.3O.sub.7 [M+Na].sup.+: 543.
EXAMPLE 181
[1549]
3-{4-[3-(4-Benzyloxy-phenoxy)-propoxy]-3-methoxy-phenyl}-2-methoxy--
propionic acid 361
[1550] The title compound was prepared from
3-[4-(3-Bromo-propoxy)-3-metho- xy-phenyl]-2-methoxy-propionic acid
(Example 175, Step B) and 4-Benzyloxy-phenol following the Standard
Procedure J. MS (ES) for C.sub.27H.sub.30O.sub.7 [M+Na].sup.+:
489.
EXAMPLE 182
[1551]
3-{4-[3-(4-Dibenzofuran-3-yl-phenoxy)-propoxy]-3-methoxy-phenyl}-2--
methoxy-propionic acid 362
[1552] The title compound was prepared from
3-[4-(3-Bromo-propoxy)-3-metho- xy-phenyl]-2-methoxy-propionic acid
(Example 175, Step B) and 4-Dibenzofuran-3-yl-phenol following the
Standard Procedure J. MS (ES) for C.sub.32H.sub.30O.sub.7
[M+NH.sub.4].sup.+:544, [M+Na].sup.+: 549.
EXAMPLE 183
[1553]
(2S)-3-{4-[4-(Biphenyl-4-yloxy)-butoxy]-phenyl}-2-methoxy-propionic
acid 363
[1554] Step A
[1555] (2S)-3-[4-(4-Hydroxy-butoxy-phenyl]-2-methoxy-propionic acid
ethyl ester 364
[1556] A mixture of 3-(4-Hydroxy-phenyl)-2-methoxy-propionic acid
ethyl ester and 3-(tert-Butyl-dimethyl-silanyloxy)-butan-1-ol were
treated under Mitsounobu coupling Standard conditions B using DIAD
and TIE. The product thus obtained was treated under Standard
Procedure E for cleaveage protected alcohols to give the title
product.
[1557] Step B
[1558] (2S)-3-[4-(4-Bromo-butoxy-phenyl]-2-methoxy-propionic acid
ethyl ester 365
[1559] The title compound was prepared from
(2S)-3-[4-(4-Hydroxy-butoxy)-p- henyl]-2-methoxy-propionic acid
ethyl ester and following the procedure described in Example 132,
Step D we obtained the title compound.
[1560] Step C
[1561]
(2S)-3-{4-[4-(Biphenyl-yloxy-butoxy]-phenyl}-2-methoxy-propionic
acid ethyl ester 366
[1562] The title compound was prepared from
(2S)-3-[4-(4-Bromo-butoxy)-phe- nyl]-2-methoxy-propionic acid ethyl
ester (Step B) and 4-phenylphenol under the Standard Procedure I to
give the product.
[1563] Step D
[1564]
2S)-3-{4-[4-(Biphenyl-4-yloxy)-butoxy]-phenyl}-2-methoxy-propionic
acid
[1565] The title compound was prepared from
(2S)-3-{4-[4-(Biphenyl-4-yloxy-
)-butoxy]-phenyl}-2-methoxy-propionic acid ethyl ester from Step C
under the standard Hydrolysis procedure C. (LiOH). .sup.1H-NMR
(200.15 MHz, CDCl.sub.3): 7.57-7.49 (m, 4H); 7.45-7.37 (m, 2H);
7.32-7.11 (m, 3H); 6.97 (d, 2H, J=8.9); 6.84 (d, 2H, J=8.9);
4.11-3.93 (m, 5H); 3.40 (s, 3H); 3.10 (dd, 1H, J=14.0, 4.3); 2.96
(dd, 1H, J=14.5, 7.0); 1.99-1.97 (m, 4H) ppm.
EXAMPLE 184
[1566]
(2S)-3-{4-[4-(4-Benzoyl-phenoxy)-butoxy]-phenyl}-2-methoxy-propioni-
c acid 367
[1567] Step A
[1568]
(2S)-3-{4-[4-(4-Benzoyl-phenoxy-butoxy]-phenyl}-2-methoxy-propionic
acid ethyl ester 368
[1569] The title compound was prepared from
(2S)-3-[4-(4-Bromo-butoxy)-phe- nyl]-2-methoxy-propionic acid ethyl
ester (Example 183, Step B) and 4-hydroxybenzophenone under the
Standard Procedure I to give the product.
[1570] Step B
[1571]
(2S)-3-{4-[4-(4-Benzoyl-phenoxy)-butoxy]-phenyl}-2-methoxy-propioni-
c acid
[1572] The title compound was prepared from
(2S)-3-{4-[4-(4-Benzoyl-phenox-
y)-butoxy]-phenyl}-2-methoxy-propionic acid ethyl ester from Step A
under the Standard hydrolysis procedure C. (LiOH). .sup.1H-NMR
(200.15 MHz; CDCl.sub.3): 7.81 (d, 2H, J=8.9), 7.75 (dd, 2H, J=8.3,
1.4), 7.6-7.4 (m, 3H), 7.15 (d, 2H, J=8.6), 6.81 (d, 2H, J=8.3),
4.2-3.9 (m, 5H), 3.37 (s, 3H), 3:08 (dd, 1H, J=14.2, 4.3), 2.94
(dd, 1H, J=14.2, 7.5), 2.1-1.9 (m, 4H) ppm.
EXAMPLE 185
[1573]
(2S)-2-Methoxy-3-{4-[4-(4-phenoxy-phenoxy)-butoxy]-phenyl}-propioni-
c acid 369
[1574] Step A
[1575]
(2S)-2-Methoxy-3-{4-[4-(4-phenoxy-phenoxy)-butoxy]-phenyl}-propioni-
c acid ethyl ester 370
[1576] The title compound was prepared from
(2S)-3-[4-(4-Bromo-butoxy)-phe- nyl]-2-methoxy-propionic acid ethyl
ester (Example 183, Step B) and 4-phenoxyphenol under the Standard
Procedure I to give the product.
[1577] Step B
[1578]
(2S)-2-Methoxy-3-{4-[4-(4-phenoxy-phenoxy)-butoxy]-phenyl}-propioni-
c acid
[1579] The title compound was prepared from
(2S)-2-Methoxy-3-{4-[4-(4-phen-
oxy-phenoxy)-butoxy]-phenyl}-propionic acid ethyl ester, from Step
A under the Standard hydrolysis procedure C. (LiOH). .sup.1H-NMR
(200.15 MHz, CDCl.sub.3): 7.4-7.2 (m, 2H), 7.15 (d, 2H, J=8.6),
7.1-6.7 (m, 9H), 4.0-3.9 (m, 5H), 3.34 (s, 3H), 3.08 (dd, 1H,
J=14.0, 4.0), 2.93 (dd, 1H, J=14.0, 7.8), 2.1-1.9 (m, 4H) ppm.
EXAMPLE 186
[1580]
(2S)-2-Methoxy-3-{4-[2-(2,3,6-trifluoro-phenoxy)ethoxy]-phenyl}-pro-
pionic acid 371
[1581] The title compound was prepared from
(2S)-3-[4-(3-hydroxy-phenyl]-2- -methoxypropionic acid linked to
Wang's Resin (Example 94, Step C) via the Mitsounobu
coupling-cleveage (Standard Procedure G) with
2-(2,3,6-Trifluoro-phenoxy)-ethanol to give the desire product.
.sup.1H-NMR (200.15 MHz, CDCl.sub.3): 7.15 (d, 2H, J=8.6), 6.9-6.8
(m, 4H), 4.51 (t, 2H, J=4.0), 4.27 (t, 2H, J=4.8), 3.97 (dd, 1H,
J=7.2, 4.3), 3.39 (s, 3H), 3.09 (dd, 1H, J=14.5, 4.5), 2.95 (dd,
1H, J=14.5, 7.5) ppm.
EXAMPLE 187
[1582]
(2S)-3-[4-(3-Benzyloxy-benzyloxy)-phenyl]-2-methoxy-propionic acid
372
[1583] The title compound was prepared from
(2S)-3-[4-(3-hydroxy-phenyl]-2- -methoxypropionic acid linked to
Wang's Resin (Example 94, Step C) via the Mitsounobu
coupling-cleveage (Standard Procedure G) with
(3-Benzyloxy-phenyl)-methanol to give the desire product.
.sup.1H-NMR (200.15 MHz, CDCl.sub.3): 7.5-7.2 (m, 5H), 7.2-6.8 (m,
8H), 5.07 (s, 2H), 5.01 (s, 2H), 3.99 (dd, 1H, J=7.0, 4.6), 3.40
(s, 3H), 3.10 (dd, 1H, J=14.2, 4.3), 2.96 (ad, 1H, J=14.5, 7.2)
ppm.
EXAMPLE 188
[1584]
3-{4-[3-(Biphenyl-4-yloxy)-propoxy]-2-methoxy-phenyl}-2-methoxy-pro-
pionic acid 373
[1585] Step A
[1586]
3-[4-(tert-Butyl-dimethyl-silanyloxy)-2-methoxy-phenyl]-3-hydroxy-2-
-methoxy-propionic acid methyl ester 374
[1587] A solution of 4-tert-butyldimethylsilanyloxy-2-methoxy
benzaldehyde (1 eq) and methyl methoxyacetate (1.25 eq) in THF (10
mL) at -78.degree. C. was added dropwise to sodium
bis(trimethylsilyl)amide (1.25 eq, 1N in THF) at -78.degree. C. The
reaction mixture was stirred for 3 h and quenched with 1N HCl (5
mL). The mixture was allowed to warm to room temperature, diluted
with water (15 mL), and extracted with ethyl acetate (3.times.15
mL). The combined organic layers were dried (MgSO.sub.4) and
concentrated. The residue was purified by silica gel column to
obtain the title compound.
[1588] Step B
[1589]
3-[4-(tert-Butyl-dimethyl-silanyloxy-2-methoxy-phenyl]-2-methoxy-pr-
opionic acid methyl ester 375
[1590] A mixture of
3-[4-(tert-Butyl-dimethyl-silanyloxy)-2-methoxy-phenyl-
]-3-hydroxy-2-methoxy-propionic acid methyl ester (1 eq),
Mesylchloride (1 eq) triethylamine (4 eq) and a catalytic amount of
DMAP (0.1 eq) in dichloromethane was stirred at room temperature
over night. The reaction mixture was diluted with ether and washed
with HCl 1N. Dried and concentrated in vacuo to give a residue
which was chromatographed in silica gel to yield a compound which
was dissolved in methanol was treated with Mg (20 eq) and stirred
until gas evolution was observed. Cooled to 0.degree. C. and
stirred for 4 hours. The solvent was removed and the residue
reconstituted in ether washed with HCl 1N and brine and
concentrated to give the title product.
[1591] Step C
[1592] 2-(4-Hydroxy-2-methoxy-benzyl)-butyric acid methyl ester
376
[1593]
3-[4-(tert-Butyl-dimethyl-silanyloxy)-2-methoxy-phenyl]-2-methoxy-p-
ropionic acid methyl ester from Step B was treated under the
Standard Procedure E to cleveage the protected silyl group and
obtained the product.
[1594] Step D
[1595]
3-{4-[3-(Biphenyl-4-yloxy)-2-propoxy]-2-methoxy-phenyl}-2-methoxy-p-
ropionic acid
[1596] A mixture solution of 2-(4-hydroxy-2-methoxy-benzyl)-butyric
acid methyl ester from Step C and 3-(biphenyl-4-yloxy)-propan-1-ol
was reacted under the Standard Mitsounobu coupling conditions B
(DIAD/toluene) to give the corresponding coupled product, which
afforded the title compound via the Standard hydrolysis procedure C
(NaOH). MS(ES) for C.sub.26H.sub.28O.sub.6 [M+NH.sub.4].sup.+:
454.
EXAMPLE 189
[1597]
3-{4-[3-(4-Benzoyl-phenoxy)-propoxy]-2-methoxy-phenyl}-2-methoxy-pr-
opionic acid 377
[1598] A mixture solution of 2-(4-Hydroxy-2-methoxy-benzyl)-butyric
acid ethyl ester from Example 188, Step C and
[4-(3-Hydroxy-propoxy)-phenyl]-p- henyl-methanone were allowed to
react under the Standard Mitsounobu coupling conditions B
(DIAD/toluene) to give the corresponding coupled product which by
the Standard hydrolysis procedure C (NaOH) yield the title
compound. MS (ES) for C.sub.27H.sub.28O.sub.7 [M+H].sup.+: 465.
EXAMPLE 190
[1599]
2-Methoxy-3-{2-methoxy-4-[3-(4-phenoxy-phenoxy)-propoxy]-phenyl}-pr-
opionic acid 378
[1600] A mixture solution of 2-(4-Hydroxy-2-methoxy-benzyl)-butyric
acid ethyl ester from Example 188, Step C and
3-(4-phenoxy-phenoxy)-propan-1-o- l were allowed to react under the
Standard Mitsounobu coupling conditions B (DIAD/toluene) to give
the corresponding coupled product which by the Standard hydrolysis
procedure C (NaOH) yielded the title compound. MS (ES) for
C.sub.26H.sub.28O.sub.7 [M+Na].sup.+: 475.
EXAMPLE 191
[1601]
3-{4-[3-(Biphenyl-4-yloxy)-propoxy]-2-chloro-phenyl}-2-methoxy-prop-
ionic acid 379
[1602] Step A
[1603] 4-Benzyloxy-2-chloro-benzoic acid benzyl ester 380
[1604] A mixture solution of 2-chloro-4-hydroxybenzoic (1 eq) acid
with benzyl bromide (2 eq) and K.sub.2CO.sub.3 (3 eq) in
acetonitrile were heated at 85.degree. C. Then filtered and
concentrated to dryness to give after chromatography in silica gel
the title compound.
[1605] Step B
[1606] (4-Benzyloxy-2-chloro-phenyl)-methanol 381
[1607] A mixture of 4-Benzyloxy-2 chloro-benzoic acid benzyl ester
from Step A with DIBAL-H 1M in toluene (2.2 eq) in THF were stirred
at room temperature for 3 hours. The quenched with tartrate
saturated solution and extracted with ethyl acetate. Concentrated
to dryness and purified by chromatography to afford the title
compound.
[1608] Step C
[1609] 4-Benzyloxy-2-chloro-benzaldehyde 382
[1610] To a solution of (4-Benzyloxy-2-chloro-phenyl)-methanol in
dichloromethane, MnO.sub.2 (10 eq) were added and the mixture
reaction stirred overnight. Filtered through a pad of celite and
purified by chromatography in silica gel to give the title
product.
[1611] Step D
[1612]
3-(4-Benzyloxy-2-chloro-phenyl)-3-hydroxy-2-methoxy-propionic acid
ethyl ester 383
[1613] A solution of 4-Benzyloxy-2-chloro-benzaldehyde (1 eq) and
methyl methoxyacetate (1.25 eq) in THF (10 mL) at -18.degree. C.
was added dropwise to sodium bis(trimethylsilyl)amide (1.25 eq, 1N
in THF) at -78.degree. C. The reaction mixture was stirred for 3 h
and quenched with 1N HCl (5 mL). The mixture was allowed to warm to
room temperature, diluted with water (15 mL), and extracted with
ethyl acetate (3.times.15 mL). The combined organic layers were
dried (MgSO.sub.4) and concentrated. The residue was purified by
silica gel column to obtained the title compound.
[1614] Step E
[1615] 3-(4-Benzyloxy-2-chloro-phenyl)-2-methoxy-propionic acid
ethyl ester 384
[1616] A mixture of
3-(4-Benzyloxy-2-chloro-phenyl)-3-hydroxy-2-methoxy-pr- opionic
acid ethyl ester (1 eq), Mesylchloride (1 eq) triethylamine (4 eq)
and a catalytic amount of DMAP (0.1 eq) in dichloromethane was
stirred at room temperature over night. The reaction mixture was
diluted with ether and washed with HCl 1N. Dried and concentrated
in vacuo to give a residue which was chromatographed in silica gel
to yield a compound which was dissolved in methanol was treated
with Mg (20 eq) and stirred until gas evolution was observed.
Cooled to 0.degree. C. and stirred for 4 hours. The solvent was
removed and the residue reconstituted in ether washed with HCl 1N
and brine and concentrated to give the title product.
[1617] Step F
[1618] 3-(2-Chloro-4-hydroxy-phenyl)-2-methoxy-propionic acid ethyl
ester 385
[1619] 3-(4-Benzyloxy-2-chloro-phenyl)-2-methoxy-propionic acid
ethyl ester in ethyl acetate was treated with Pd(C) and H.sub.2
under balloon pressure. Then filtered through celite and
concentrated to give the title compound.
[1620] Step G
[1621]
3-{4-[3-(Biphenyl-4-yloxy)-propoxy]-2-chloro-phenyl}-2-methoxy-prop-
ionic acid 386
[1622] A mixture solution of
3-(2-Chloro-4-hydroxy-phenyl)-2-methoxy-propi- onic acid ethyl
ester from Step F and 3-(Biphenyl-4-yloxy)-propan-1-ol were allowed
to react under the Standard Mitsounobu coupling conditions B
(DIAD/toluene) to give the corresponding coupled product which by
the Standard hydrolysis procedure C (NaOH) yield the title
compound. MS (ES) for C.sub.25H.sub.25ClO.sub.5 [M+NH.sub.4].sup.+:
458.
EXAMPLE 192
[1623]
3-[2-Chloro-4-[3-(4-phenoxy-phenoxy)-propoxy]-phenyl}-2-methoxy-pro-
pionic acid 387
[1624] A mixture solution of
3-(2-Chloro-4-hydroxy-phenyl)-2-methoxy-propi- onic acid ethyl
ester from Example 191, Step F and 3-(4-phenoxy-phenoxy)-p-
ropan-1-ol were allowed to react under the Standard Mitsounobu
coupling conditions B (DIAD/toluene) to give the corresponding
coupled product which by the Standard hydrolysis procedure C (NaOH)
yield the title compound. MS (ES) for C.sub.25H.sub.25ClO.sub.6
[M+NH.sub.4].sup.+: 474.
EXAMPLE 193
[1625]
3-{4-[3-(4-Benzoyl-phenoxy)-propoxy]-2-chloro-phenyl}-2-methoxy-pro-
pionic acid 388
[1626] A mixture solution of
3-(2-Chloro-4-hydroxy-phenyl)-2-methoxy-propi- onic acid ethyl
ester from Example 132, Step F and [4-(3-Hydroxy-propoxy)--
phenyl]-phenyl-methanone were allowed to react under the Standard
Mitsounobu coupling conditions B (DIAD/toluene) to give the
corresponding coupled product which by the Standard hydrolysis
procedure C (NaOH) yield the title compound. MS (ES) for
C.sub.26H.sub.25ClO.sub.6 [M+H].sup.+: 469.
EXAMPLE 194
[1627]
(2S)-4-{3-[4-(2-Carboxy-2-methoxy-ethyl)-phenoxy]-propoxy}-benzoic
acid 389
[1628] Step A
[1629]
(2S)-4-{3-[4-(2-Ethoxycarbonyl-2-methoxy-ethyl)-phenoxy]-propoxy}-b-
enzoic acid benzyl ester 390
[1630] (2S)-3-[4-(3-Hydroxy-propoxy)-phenyl]-2-methoxy-propionic
acid ethyl ester from 0, Step B and 4-Hydroxy-benzoic acid benzyl
ester were treated under Mitsounobu Standard coupling conditions B
to give the title compound.
[1631] Step B
[1632]
(2S)-4-{3-[4-(2-Carboxy-2-methoxy-ethyl)-phenoxy)-propoxy}-benzoic
acid
[1633] The title compound was prepared from
(2S)-4-{3-[4-(2-Ethoxycarbonyl-
-2-methoxy-ethyl)-phenoxy]-propoxy}-benzoic acid benzyl ester (Step
A) by Standard Hydrolysis procedure C (NaOH). MS (ES) for
C.sub.20H.sub.22O.sub.7 [M+Na].sup.+: 397.
EXAMPLE 195
[1634]
(2S)-3-(4-[3-(4-Dibenzothiophen-4-yl-phenoxy)-propoxy]-phenyl}-2-me-
thoxy-propionic acid 391
[1635] Step A
[1636]
(2S)-3-{4-[3-(4-Dibenzothiophen-4-yl-phenoxy)-propoxy]-phenyl}-2-me-
thoxy-propionic acid ethyl ester 392
[1637] (2S)-3-[4-(3-Hydroxy-propoxy)-phenyl]-2-methoxy-propionic
acid ethyl ester from Example 171, Step B and
4-Dibenzothiophen-4-yl-phenol were treated under Mitsounobu
Standard coupling conditions B to give the title compound.
[1638] Step B
[1639]
(2S)-3-{4-[3-(4-Dibenzothiophen-4-yl-phenoxy)-propoxy]-phenyl-2-met-
hoxy-propionic acid
[1640] The title compound was prepared from
(2S)-3-{4-[3-(4-Dibenzothiophe-
n-4-yl-phenoxy)-propoxy]-phenyl}-2-methoxy-propionic acid ethyl
ester (Step A) by Standard Hydrolysis procedure C (NaOH). MS (ES)
for C.sub.3H.sub.28O.sub.5S [M+NH.sub.4].sup.+: 530.
EXAMPLE 196
[1641]
(2S)-3-{4-[3-(4'-Hydroxy-biphenyl-4-yloxy)-propoxy]-phenyl}-2-metho-
xy-propionic acid 393
[1642] Step A
[1643]
(2S)-3-(4-{3-[4'-(tert-Butyl-dimethyl-silanyloxy)-biphenyl-4-yloxy]-
-propoxy}-phenyl)-2-methoxy-propionic acid ethyl ester 394
[1644] (2S)-3-[4-(3-Bromo-propoxy)-phenyl]-2-methoxy-propionic acid
ethyl ester from Example 173, Step A, and
4-(tert-Butyl-dimethyl-silanyloxy)-bi- phenyl-4-ol were treated
with CsCO.sub.3 (3 eq) in DMF and stirred at room temperature over
night.
[1645] Filtered and concentrated in vacuo to give the title
compound.
[1646] Step B
[1647]
(2S)-3-{4-[3-(4'-Hydroxy-biphenyl-4-yloxy)-propoxy]-phenyl}-2-metho-
xy-propionic acid
[1648] The title compound was prepared from
(2S)-3-(4-{3-[4'-(tert-Butyl-d-
imethyl-silanyloxy)-biphenyl-4-yloxy]-propoxy}-phenyl)-2-methoxy-propionic
acid ethyl t: ester (Step A) by Standard Hydrolysis procedure C
(NaOH). MS (ES) for C.sub.25H.sub.26O.sub.6 [M+Na].sup.+: 445.
EXAMPLE 197
[1649]
(2S)-4'-{3-[4-(2-Carboxy-2-methoxy-ethyl)-phenoxy]-propoxy}-bipheny-
l-4-carboxylic acid 395
[1650] Step A
[1651]
(2S)-4'-{3-[4-(2-Ethoxycarbonyl-2-methoxy-ethyl)-phenoxy]-propoxy}--
biphenyl-4-carboxylic acid methyl ester 396
[1652] (2S)-3-[4-(3-Hydroxy-propoxy)-phenyl]-2-methoxy-propionic
acid ethyl ester from Example 171, Step B and
4'-Hydroxy-biphenyl-4-carboxylic acid methyl ester were treated
under Mitsounobu Standard coupling conditions B to give the title
compound.
[1653] Step B
[1654]
(2S)-4'-{3-[4-(2-Carboxy-2-methoxy-ethyl)-phenoxy]-propoxy}-bipheny-
l-4-carboxylic acid
[1655] The title compound was prepared from
(2S)-4'-{3-[4-(2-Ethoxycarbony-
l-2-methoxy-ethyl)-phenoxy]-propoxy}-biphenyl-4-carboxylic acid
methyl ester (Step A) by Standard Hydrolysis procedure C (NaOH). MS
(ES) for C.sub.26H.sub.26O.sub.7 [M+NH.sub.4].sup.+: 468,
[M+Na].sup.+: 473.
EXAMPLE 198
[1656]
(2S)-3-{4-[2-(4-Benzoyl-phenoxy)-cyclohexyloxy]-phenyl}-2-methoxy-p-
ropionic acid 397
[1657] The title compound was prepared from
(2S)-3-(4-hydroxyphenyl)-2-met- hoxy-propionic acid linked to
Wang's resin Example 94, Step C) via Mitsounobu coupling (Standard
Procedure F) to give
3-[4-(2-Hydroxy-cyclohexyloxy)-phenyl]-2-methoxy-propionic acid
linked to the resin. A second Mitsounobu coupling reaction with
4-hydroxybenzophenone via Standard Procedure G allow us to get the
title compound. .sup.1H-NMR (CDCl.sub.3, 200 MHz): 7.75 (d, 4H,
J=8.6); 7.57-7.43 (m, 3H); 7.13 (d, 2H, J=8.9); 6.89 (d, 2H,
J=9.1); 6.79 (d, 2H, J=8.6); 4.53-36 (m, 2H); 4.04-3.99 (m, 1H);
3.43 (s, 3H); 3.08-2.94 (m, 2H); 1.38-1.29 (m, 8H) ppm
EXAMPLE 199
[1658]
(2S)-3-(4-{2-[4-(4-Fluoro-benzoyl)-phenoxy]-cyclohexyloxy}-phenyl)--
2-methoxy-propionic acid 398
[1659] The title compound was prepared from
(2S)-3-(4-hydroxyphenyl)-2-met- hoxy-propionic acid linked to
Wang's resin (Example 94, Step C) via Mitsounobu coupling (Standard
Procedure I) to give
3-[4-(2-Hydroxy-cyclohexyloxy)-phenyl]-2-methoxy-propionic acid
linked to the resin. A second Mitsounobu coupling reaction with
4-fluoro-4'-hydroxybenzophenone via Standard Procedure G allows us
to get the title compound. .sup.1H-NMR (CDCl.sub.3, 200 MHz):
7.83-7.69 (m, 4H); 7.19-7.11 (m, 4H); 6.89 (d, 2H, J=8.9); 6.79 (d,
2H, J=8.6); 4.53-4.33 (m, 2H); 4.02 (dd, 1H, J=6.5, 4.8); 3.43 (s.
3M); 3.10 (dd, 1H, J=14.4, 4.8), 2.98 (dd, 1H, J=14.4, 6.5);
1.38-1.29 (m, 8H) ppm.
EXAMPLE 200
[1660]
(2S)-3-(4-{3-[3-4-Fluoro-phenyl)-benzofuran-6-yloxy]-propoxy}-pheny-
l)-2-methoxy-propionic acid 399
[1661] (2S)-3-[4-(3-Bromo-propoxy)-phenyl]-2-methoxy-propionic acid
ethyl ester from Example 173, Step A was treated with
3-(4-Fluoro-phenyl)-benzo- furan-6-ol under the Standard Procedure
J. The compound thus obtained was allowed to react under Standard
hydrolysis procedure C (NaOH) to give the title compound. MS(ES)
for C.sub.27H.sub.25FO.sub.6 [M+NH.sub.4].sup.+: 482, [M+Na].sup.+:
487, [M+H].sup.+: 464.
EXAMPLE 201
[1662]
(2S)-2-Methoxy-3-{4-[3-(5,6,7,8-tetrahydro-naphthalen-2-yloxy)-prop-
oxy]-phenyl}-propionic acid 400
[1663] (2S)-3-[4-(3-Bromo-propoxy)-phenyl]-2-methoxy-propionic acid
ethyl ester from Example 173, Step A was treated with
5,6,7,8-Tetrahydro-naphth- alen-2-ol under the Standard Procedure
J. The compound thus obtained was allowed to react under Standard
Hydrolysis Procedure C (NaOH) to give the title compound. MS(ES)
for C.sub.23H.sub.28NO.sub.5 [M+Na].sup.+: 407, [M+H].sup.+:
385.
EXAMPLE 202
[1664]
(2S)-3-{4-[3-(4-Benzyloxy-phenoxy)-propoxy]-phenyl}-2-methoxy-propi-
onic acid 401
[1665] (2S)-3-[4-(3-Bromo-propoxy)-phenyl]-2-methoxy-propionic acid
ethyl ester from Example 173, Step A was treated with
4-Benzyloxy-phenol under the Standard Procedure J. The compound
thus obtained was allowed to react under Standard hydrolysis
procedure C (NaOH) to give the title compound. MS(ES) for
C.sub.26H.sub.28O.sub.6 [M-H].sup.-: 435.
EXAMPLE 203
[1666]
(2S)-3-{4-[3-(4-Butoxy-phenoxy)-propoxy]-phenyl}-2-methoxy-propioni-
c acid 402
[1667] (2S)-3-[4-(3-Bromo-propoxy)-phenyl]-2-methoxy-propionic acid
ethyl ester from Example 173, Step A was treated with
4-Butoxy-phenol under the Standard Procedure J. The compound thus
obtained was allowed to react under Standard hydrolysis procedure C
(NaOH) to give the title compound. MS(ES) for CH.sub.30O.sub.6
M+NH.sub.4].sup.+: 420, [M+Na].sup.+: 425, [M+H].sup.+: 403.
EXAMPLE 204
[1668]
(2S)-3-{4-[3-(4-Heptyloxy-phenoxy)-propoxy]-phenyl}-2-methoxy-propi-
onic acid 403
[1669] (2S)-3-[(3-Bromo-propoxy)-phenyl]-2-methoxy-propionic acid
ethyl ester from Example 173, Step A was treated with
4-Heptyloxy-phenol under the Standard Procedure J. The compound
thus obtained was allowed to react under Standard hydrolysis
procedure C (NaOH) to give the title compound. MS(ES) for
C.sub.36H.sub.36O.sub.6 [M+Na].sup.+: 467, [M+H].sup.+: 445.
EXAMPLE 205
[1670]
(2S)-3-{4-[3-(6-Benzoyl-naphthalen-2-yloxy)-propoxy]-phenyl}-2-meth-
oxy-propionic acid 404
[1671] (2S)-3-[4-(3-Bromo-propoxy)-phenyl]-2-methoxy-propionic acid
ethyl ester from Example 173, Step A was treated with
(6-Hydroxy-naphthalen-2-y- l)-phenyl-methanone under the Standard
Procedure J. The compound thus obtained was allowed to react under
Standard hydrolysis procedure C NaOH) to give the title compound.
MS(ES) for C.sub.30H.sub.2SO.sub.6 [M+Na].sup.+: 507, [M+H].sup.+:
485.
EXAMPLE 206
[1672]
(2S)-3-[4-3-(Benzo[1,3]dioxol-5-yloxy)-propoxy]-phenyl}-2-methoxy-p-
ropionic acid 405
[1673] (2S)-3-[4-(3-Bromo-propoxy)-phenyl]-2-methoxy-propionic acid
ethyl ester from Example 173, Step A was treated with
Benzo[1,3]dioxol-5-ol under the Standard Procedure J. The compound
thus obtained was allowed to react under Standard hydrolysis
procedure C (NaOH) to give the title compound. MS(ES) for
C.sub.20H.sub.22O.sub.7 [M+Na].sup.+: 397, [M+H].sup.+: 375.
EXAMPLE 207
[1674]
(2S)-3-{4-[3-(9H-Fluoren-2-yloxy)-propoxy]-phenyl}-2-methoxy-propio-
nic acid 406
[1675] (2S)-3-[4-(3-Bromo-propoxy)-phenyl]-2-methoxy-propionic acid
ethyl ester from Example 173, Step A was treated with
9H-Fluoren-2-ol under the Standard Procedure S. The compound thus
obtained was allowed to react under Standard hydrolysis procedure C
(NaOH) to give the title compound. MS(ES) for
C.sub.26H.sub.26O.sub.5 [M+Na].sup.+: 441.
EXAMPLE 208
[1676]
(2S)-2-Methoxy-3-{4-[3-(4-octyl-phenoxy-propoxy]-phenyl}-propionic
acid 407
[1677] (2S)-3-[4-(3-Bromo-propoxy)-phenyl]-2-methoxy-propionic acid
ethyl ester from Example 173, Step A was treated with
4-Octyl-phenol under the Standard Procedure J. The compound thus
obtained was allowed to react under Standard hydrolysis procedure C
(NaOH) to give the title compound. MS(ES) for
C.sub.27H.sub.38O.sub.5 [M+Na].sup.+: 466.
EXAMPLE 209
[1678]
(2S)-2-Methoxy-3-{4-[3-(naphthalen-1-yloxy-propoxy]-phenyl}-propion-
ic acid 408
[1679] (2S)-3-[4-(3-Bromo-propoxy)-phenyl]-2-methoxy-propionic acid
ethyl ester from Example 173, Step A was treated with
Naphthalen-1-ol under the Standard Procedure J., The compound thus
obtained was allowed to react under Standard hydrolysis procedure C
(NaOH) to give the title compound. MS(ES) for
C.sub.23H.sub.24O.sub.5 [M+Na].sup.+: 403, [M+H].sup.+: 381.
EXAMPLE 210
[1680]
(2S)-3-{4-[3-(1H-Indol-7-yloxy)-propoxy]-phenyl}-2-methoxy-propioni-
c acid 409
[1681] (2S)-3-[4-(3-Bromo-propoxy)-phenyl]-2-methoxy-propionic acid
ethyl ester from Example 173, Step A was treated with 1H-Indol-7-ol
under the Standard Procedure J. The compound thus obtained was
allowed to react under Standard hydrolysis procedure C (NaOH) to
give the title compound. MS(ES) for C.sub.21H.sub.23NO.sub.5
[M+Na].sup.+: 392; [M+H].sup.+: 370.
EXAMPLE 211
[1682]
(2S)-3-{4-[3-(4'-Fluoro-biphenyl-4-yloxy)-propoxy]-phenyl}-2-methox-
y-propionic acid 410
[1683] Step A
[1684] Preparation of p-Iodophenol Linked to the Wang's Resin
411
[1685] Wang resin, (1 eq), p-iodophenol (4:5 eq) and PPh.sub.3 (5-8
eq) were suspended in a vial and cooled to 0.degree. C. then DIAD
was added (5 eq). The mixture reaction was allowed to get room
temperature and stirred overnight. Filtered of and washed with
MeOH--CH.sub.2Cl.sub.2-THF- -HClaq and CH.sub.2Cl.sub.2 to give the
product.
[1686] Step B
[1687] 4'-Fluoro-biphenyl-4-ol 412
[1688] A mixture of p-Iodophenol linked to the Wang's resin from
Step A (1 eq), 4-fluorobenzene boronic acid (6 eq), K.sub.2CO.sub.3
(12 eq) and Pd(OAc).sub.2 (0.5 eq) were suspended in a mixture of
dioxane/water (6/1) and the mixture was heated at 100.degree. C.
and stirring for 36 hours. The resin was washed with DMF/H.sub.2O
and MeOH/HCl diluted and MeOH/CH.sub.2Cl.sub.2. After it was dried,
was suspended in dichloromethane, and TFA 95% was added. The
mixture was stirred at room temperature for 30 min then filtered
and washed with MeOH and dichloromethane. The solvents were
concentrated to dryness to give the title product.
[1689] Step C
[1690]
(2S)-3-{4-[3-(4'-Fluoro-biphenyl-4-yloxy)-propoxy]-phenyl}-2-methox-
y-propionic acid
[1691] (2S)-3-[4-(3-Bromo-propoxy)-phenyl]-2-methoxy-propionic acid
ethyl ester from Example 173, Step A was treated with
4'-Fluoro-biphenyl-4-ol from Step B under the Standard Procedure J.
The compound thus obtained was allowed to react under Standard
hydrolysis procedure C (NaOH) to give the title compound. MS(ES)
for C.sub.25H.sub.25F.sub.05 [M+NH.sub.4].sup.+: 442, [M+Na].sup.+:
447.
EXAMPLE 212
[1692]
(2S)-3-{4-[3-(4'-Chloro-biphenyl-4-yloxy-propoxy]-phenyl}-2-methoxy-
-propionic acid 413
[1693] Step A
[1694] 4-chlorobiphenyl-4-ol 414
[1695] The title compound was prepared following the procedure
described in Example 211, Step B with 4-chlorophenyl boronic
acid.
[1696] Step B
[1697]
(2S)-3-{4-[3-(4'-Chloro-biphenyl-4-yloxy)-propoxy]-phenyl}-2-methox-
y-propionic acid
[1698] (2S)-3-[4-(3-Bromo-propoxy)-phenyl]-2-methoxy-propionic acid
ethyl ester from Example 173, Step A was treated with
chloro-biphenyl-4-ol from Step A under the Standard Procedure J.
The compound thus obtained was allowed to react under Standard
hydrolysis procedure C (NaOH) to give the title compound. MS(ES)
for C.sub.25H.sub.25ClO.sub.5 [M+Na].sup.+: 463, [M+H].sup.+:
441.
EXAMPLE 213
[1699]
(2S)-3-{4-[3-(3',5'-Bis-trifluoromethyl-biphenyl-4-yloxy)-propoxy]--
phenyl}-2-methoxy-propionic acid 415
[1700] Step A
[1701] 3',5'-Bis-trifluoromethyl-biphenyl-4-ol 416
[1702] The title compound was prepared following the procedure
described in Example 211, Step B with
3,5-bis(trifluoromethyl)-phenyl boronic acid.
[1703] Step B
[1704]
(2S)-3-{4-[3-(3',5'-Bis-trifluoromethyl-biphenyl-4-yloxy)-propoxy]--
phenyl}-2-methoxy-propionic acid
[1705] (2S)-3-[4-(3-Bromo-propoxy)-phenyl]-2-methoxy-propionic acid
ethyl ester from Example 173, Step A was treated with
3,5-Bis-trifluoromethyl-b- iphenyl-4-ol from Step A under the
Standard Procedure J. The compound thus obtained was allowed to
react under Standard hydrolysis procedure C (NaOH) to give the
title compound. MS(ES) for C.sub.27H.sub.24F.sub.6O.su- b.5
[M+Na].sup.+: 565, [M+H].sup.+: 543.
EXAMPLE 214
[1706]
(2S)-3-{4-[3-(4-Dibenzofuran-4-yl-phenoxy)-propoxy]-phenyl}-2-metho-
xy-propionic acid 417
[1707] Step A
[1708] 4-Dibenzofuran-yl-phenol 418
[1709] The title compound was prepared following the procedure
described in Example 211, Step B with 4-benzofurane boronic
acid
[1710] Step B
[1711]
(2S)-3-{4-[3-(4-Dibenzofuran-4-yl-phenoxy)-propoxy]-phenyl}-2-metho-
xy-propionic acid
[1712] (2S)-3-[4-(3-Bromo-propoxy)-phenyl]-2-methoxy-propionic acid
ethyl ester from 0, Step A was treated with
4-Dibenzofuran-4-yl-phenol from Step A under the Standard Procedure
J. The compound thus obtained was allowed to react under Standard
hydrolysis procedure C (NaOH) to give the title compound. MS(ES)
for C.sub.3H.sub.30O.sub.6 [M+Na].sup.+: 519.
EXAMPLE 215
[1713]
(2S)-2-Methoxy-3-{4-[3-(4'-phenoxy-biphenyl-4-yloxy)-propoxy]-pheny-
l}-propionic acid 419
[1714] Step A
[1715] 4'-phenoxy-biphenyl-4-ol 420
[1716] The title compound was prepared following the procedure
described in Example 211, Step B with 4-phenoxyphenyl boronic
acid.
[1717] Step B
[1718]
(2S)-2-Methoxy-3-{4-[3-(4'-phenoxy-biphenyl-4-yloxy)-propoxy]-pheny-
l}-propionic acid
[1719] (2S)-3-[4-(3-Bromo-propoxy)-phenyl]-2-methoxy-propionic acid
ethyl ester from Example 173, Step A was treated with
4'-phenoxy-biphenyl-4-ol from Step A under the Standard Procedure
J. The compound thus obtained was allowed to react under Standard
hydrolysis procedure C (NaOH) to give the title compound. MS(ES)
for C.sub.3H.sub.30O.sub.6 [M+NH.sub.4].sup.+: 516, [M+Na].sup.+:
521.
EXAMPLE 216
[1720]
(2S)-2-Methoxy-3-{4-[3-(4-thiophen-2-yl-phenoxy)-propoxy]-phenyl}-p-
ropionic acid 421
[1721] Step A
[1722] 4-Thiophen-2-yl-phenol 422
[1723] The title compound was prepared following the procedure
described in Example 211, Step B with tiophene-2-boronic acid
[1724] Step B
[1725]
(2S)-2-Methoxy-3-{4-[3-(4-thiophen-2-yl-phenoxy)-propoxy]-phenyl}-p-
ropionic acid
[1726] 2S)-3-[4-(3-Bromo-propoxy)-phenyl]-2-methoxy-propionic acid
ethyl ester from Example 173, Step A was treated with
4-Thiophen-2-yl-phenol from Step A under the Standard Procedure J.
The compound thus obtained was allowed to react under Standard
hydrolysis procedure C (NaOH) to give the title compound. MS(ES)
for C.sub.23H.sub.24O.sub.5 [M+NH.sub.4].sup.+: 430, [M+Na].sup.+:
435.
EXAMPLE 217
[1727]
(2S)-3-{4-[3-(3'-Chloro-biphenyl-4-yloxy)-propoxy]-phenyl}-2-methox-
y-propionic acid 423
[1728] Step A
[1729] 3'-Chloro-biphenyl-4-ol 424
[1730] The title compound was prepared following the procedure
described in Example 211, Step B with 3-chlorophenyl boronic
acid.
[1731] Step B
[1732]
(2S)-3-{4-[3-(3-Chloro-biphenyl-4-yloxy)-propoxy]-phenyl}-2-methoxy-
-propionic
[1733] (2S)-3-[4-(3-Bromo-propoxy)-phenyl]-2-methoxy-propionic acid
ethyl ester from 0, Step A was treated with 3'-Chloro-biphenyl-4-ol
from Step A under the Standard Procedure J. The compound thus
obtained was allowed to react under Standard hydrolysis procedure C
(NaOH) to give the title compound. MS(ES) for
C.sub.25H.sub.25ClO.sub.5 [M+NH.sub.4].sup.+: 458, [M+Na].sup.+:
463.
EXAMPLE 218
[1734]
(2S)-3-{4-[3-(2'-Chloro-biphenyl-4-yloxy)-propoxy]-phenyl}-2-methox-
y-propionic acid 425
[1735] Step A
[1736] 2'-Chloro-biphenyl-4-ol 426
[1737] The title compound was prepared following the procedure
described in Example 211, Step B with 2-chlorophenyl boronic
acid
[1738] Step B
[1739]
(2S)-3-{4-[3-(2'-Chloro-biphenyl-4-yloxy)-propoxy]-phenyl}-2-methox-
y-propionic acid
[1740] (2S)-3-{4-(3-Bromo-propoxy)-phenyl]-2-methoxy-propionic acid
ethyl ester from Example 173, Step A was treated with
2-Chloro-biphenyl-4-ol from Step A under the Standard Procedure J.
The compound thus obtained was allowed to react under
[1741] Standard hydrolysis procedure C (NaOH) to give the title
compound. MS(ES) for C.sub.25H.sub.25ClO.sub.5 [M+NH.sub.4].sup.+:
458, [M+Na].sup.+: 463.
EXAMPLE 219
[1742]
(2S)-3-{4-[3-(2'-Fluoro-biphenyl-4-yloxy)-propoxy]-phenyl}-2-methox-
y-propionic acid 427
[1743] Step A
[1744] 2'-Fluoro-biphenyl-4-ol 428
[1745] The title compound was prepared following the procedure
described in Example 211, Step B with 2-fluorophenyl boronic
acid
[1746] Step B
[1747]
(2S)-3-{4-[3-(2'-Fluoro-biphenyl-4-yloxy)-propoxy]-phenyl}-2-methox-
y-propionic acid
[1748] (2S)-3-[4-(3-Bromo-propoxy)-phenyl]-2-methoxy-propionic acid
ethyl ester from Example 173, Step A was treated with
2-fluoro-biphenyl 1 from Step A under the Standard Procedure J. The
compound thus obtained was allowed to react under Standard
hydrolysis procedure C (NaOH) to give the title compound. MS(ES)
for C.sub.25H.sub.25FO.sub.5 [M+NH.sub.4].sup.+: 442, [M+Na].sup.+:
447.
EXAMPLE 220
[1749]
(2S)-3-{4-[3-(4-Benzo[1,3]dioxol-5-yl-phenoxy)-propoxy]-phenyl}-2-m-
ethoxy-propionic acid 429
[1750] Step A
[1751] 4-Benzo[1,3]dioxol-5-yl-phenol 430
[1752] The title compound was prepared following the procedure
described in Example 211, Step B with 3,4-methylenedioxophenyl
boronic acid
[1753] Step B
[1754]
(2S)-3-{4-[3-(4-Benzo[1,3]dioxol-5-yl-phenoxy)-propoxy]-phenyl}-2-m-
ethoxy-propionic acid
[1755] (2S)-3-[4-(3-Bromo-propoxy)-phenyl]-2-methoxy-propionic acid
ethyl ester from Example 173, Step A was treated with
4-Benzo[1,3]dioxol-5-yl-p- henol from Step A under the Standard
Procedure J. The compound thus obtained was allowed to react under
Standard hydrolysis procedure C (NaOH) to give the title compound.
MS(ES) for C.sub.26H.sub.26O.sub.7 [M+NH.sub.4].sup.+: 468,
[M+Na].sup.+: 473.
EXAMPLE 221
[1756]
2S)-3-{4-[3-(4'-tert-Butyl-biphenyl-4-yloxy)-propoxy]-phenyl}-2-met-
hoxy-propionic acid 431
[1757] Step A
[1758] 4'-tert-Butyl-biphenyl-4-ol 432
[1759] The title compound was prepared following the procedure
described in Example 211, Step B with 4-tert-butylphenyl boronic
acid
[1760] Step B
[1761]
(2S)-3-{4-[3-(4'-tert-Butyl-biphenyl-4-yloxy)-propoxy]-phenyl}-2-me-
thoxy-propionic acid
[1762] (2S)-3-[4-(3-Bromo-propoxy)-phenyl]-2-methoxy-propionic acid
ethyl ester from Example 173, Step A was treated with
4'-tert-Butyl-biphenyl-4-- ol from Step A under the Standard
Procedure J. The compound thus obtained was allowed to react under
Standard hydrolysis procedure C (NaOH) to give the title compound.
MS(ES) for C.sub.29H.sub.34O.sub.5 [M+NH.sub.4].sup.+: 0.480,
[M+Na].sup.+: 485.
EXAMPLE 222
[1763]
(2S)-2-Methoxy-3-{4-[3-(3'-trifluoromethoxy-biphenyl-4-yloxy)-propo-
xy]-phenyl}-propionic acid 433
[1764] Step A
[1765] 3'-Trifluoromethoxy-biphenyl-4-ol 434
[1766] The title compound was prepared following the procedure
described in Example 211, Step B with 3-trifluoromethoxybenzebe
boronic acid
[1767] Step B
[1768]
(2S)-2-Methoxy-3-{4-[3-(3'-trifluoromethoxy-biphenyl-4-yloxy)-propo-
xy]-phenyl}-propionic acid
[1769] (2S)-3-[4-(3-Bromo-propoxy)-phenyl]-2-methoxy-propionic acid
ethyl ester from Example 173, Step A was treated with
3'-Trifluoromethoxy-biphe- nyl-4-ol from Step A under the Standard
Procedure J. The compound thus obtained was allowed to react under
Standard hydrolysis procedure C (NaOH) to give the title compound.
MS(ES) for C.sub.26H.sub.25F.sub.3O.su- b.6 [M+Na].sup.+: 513,
[M+H].sup.+: 491.
EXAMPLE 223
[1770]
(2S)-2-Methoxy-3-{4-[3-(4'-trifluoromethoxy-biphenyl-4-yloxy)-propo-
xy]-phenyl}-propionic acid 435
[1771] Step A
[1772] 4'-Trifluoromethoxy-biphenyl-4-ol 436
[1773] The title compound was prepared following the procedure
described in Example 211, Step B with 4-trifluoromethoxybenzebe
boronic acid
[1774] Step B
[1775]
(2S)-2-Methoxy-3-{4-[3-(3'-trifluoromethoxy-biphenyl-4-yloxy)-propo-
xy]-phenyl}-propionic acid
[1776] (2S)-3-[4-(3-Bromo-propoxy)-phenyl]-2-methoxy-propionic acid
ethyl ester from Example 173, Step A was treated with
4'-Trifluoromethoxy-biphe- nyl-4-ol from Step A under the Standard
Procedure J. The compound thus obtained was allowed to react under
Standard hydrolysis procedure C (NaOH) to give the title compound.
MS(ES) for C.sub.26F.sub.3O.sub.6 [M+NH.sub.4].sup.+: 508,
[M+Na].sup.+: 513.
EXAMPLE 224
[1777]
(2S)-3-(4-{3-[4-(2-Chloro-benzoylamino)-phenoxy]-propoxy}-phenyl)-2-
-methoxy-propionic acid 437
[1778] Step A
[1779] p-Aminophenol Linked to Wang's Resin
[1780] A suspension of Wang's resin in THF/CH.sub.2Cl.sub.2 was
treated with DIAD (5 eq), Ph3P (5 eq) and p-nitrophenol (5 eq). The
mixture was stirred overnight and then the resin was filtered
through and washed with MeOH/CH.sub.2Cl.sub.2 several times. After
dried the resin was suspended in DAD and treated with SnCl2 (10 eq)
and stirred again overnight. Filtered and washed with
MeOH/CH.sub.2Cl.sub.2 several times and dried to give th
product.
[1781] Step B
[1782] 2-Chloro-N-(4-hydroxy-phenyl)-benzamide 438
[1783] A suspension of p-aminophenol linked to the Wang's resin
from Step A (1 eq) in dichloromethane was treated with
triethylamine (2 ml/mmol) and 2-chloro-benzoyl chloride (10 eq).
The mixture reaction was stirred for 1 hour and then the resin was
filtered, washed with MeOH/CH.sub.2Cl.sub.2 several times and
dried. The resin was then treated with TEA 95% H.sub.2O 5% and
stirred at room temperature for 30 minutes. Filtered and washed
with dichloromethane/methanol and concentrated to dryness to afford
the title compound.
[1784] Step C
[1785]
(2)-3-{3-[4-(2-Chloro-benzoylamino)-phenoxy]-propoxy}-phenyl)-2-met-
hoxy-propionic acid
[1786] (2S)-3-[4-(3-Bromo-propoxy)-phenyl]-2-methoxy-propionic acid
ethyl ester from Example 173, Step A was treated with
2-Chloro-N-(4-hydroxy-phe- nyl)-benzamide from Step B under the
Standard Procedure 3. The compound thus obtained was allowed to
react under Standard hydrolysis procedure C (NaOH) to give the
title compound. MS(ES) for C.sub.26H.sub.26ClNO.sub.6 [M+H].sup.+:
484.
EXAMPLE 225
[1787]
(2S)-2-Methoxy-3-(4-{3-[4-(2-methoxy-benzoylamino)-phenoxy]-propoxy-
}-phenyl)-propionic acid 439
[1788] Step A
[1789] N-(4-Hydroxy-phenyl)-2-methoxy-benzamide 440
[1790] The title compound was prepared following the procedure
described in 0, Step B with 2-methoxy-benzoyl chloride.
[1791] Step B
[1792]
(2S)-2-Methoxy-3-(4-{3-[4-(2-methoxy-benzoylamino)-phenoxy]-propoxy-
}-phenyl)-propionic acid
[1793] (2S)-3-[4-(3-Bromo-propoxy)-phenyl]-2-methoxy-propionic acid
ethyl ester, from Example 173, Step A was treated with
N-(4-Hydroxy-phenyl)-2-m- ethoxy-benzamide from Step A under the
Standard Procedure J. The compound thus obtained was allowed to
react under Standard hydrolysis procedure C (NaOH) to give the
title compound. MS(ES) for C.sub.27H.sub.29NO.sub.7 [+H].sup.+:
480.
EXAMPLE 226
[1794]
(2S)-3-(4-{3-[4-(2,2-Dimethyl-propionylamino)-phenoxy]-propoxy}-phe-
nyl)-2-methoxy-propionic acid 441
[1795] Step A
[1796] N-(4-Hydroxy-phenyl)-2,2-dimethyl-propionamide 442
[1797] The title compound was prepared following the procedure
described in Example 224, Step B with 2,2-Dimethyl-propionyl
chloride.
[1798] Step B
[1799]
(2S)-3-(4-{3-[4-(2,2-Dimethyl-propionylamino)-phenoxy]-propoxy}-phe-
nyl)-2-methoxy-propionic acid
[1800] (2S)-3-[4-(3-Bromo-propoxy)-phenyl]-2-methoxy-propionic acid
ethyl ester from Example 173, Step A was treated with
N-(4-Hydroxy-phenyl)-2,2-- dimethyl-propionamide from Step A under
the Standard Procedure J. The compound thus obtained was allowed to
react under Standard hydrolysis procedure C (NaOH) to give the
title compound. MS(ES) for C.sub.24H.sub.31NO.sub.6 [M+H].sup.+:
430.
EXAMPLE 227
[1801]
(2S)-3-(4-{3-[4-(3-[4-(3-Fluoro-benzoylamino)-phenoxy]-propoxy}-phe-
nyl)-2-methoxy-propionic acid 443
[1802] Step A
[1803] 3-Fluoro-N-(4-hydroxy-phenyl)benzamide 444
[1804] The title compound was prepared following the procedure
described in Example 224, Step B with 3-Fluoro-benzoyl
chloride.
[1805] Step B
[1806]
(2S)-3-(4-{3-[4-(3-Fluoro-benzoylamino)-phenoxy]-propoxy}-phenyl)-2-
-methoxy-propionic acid
[1807] (2S)-3-[4-(3-Bromo-propoxy)-phenyl]-2-methoxy-propionic acid
ethyl ester from Example 173, Step A was treated with
3-Fluoro-N-(4-hydroxy-phe- nyl)-benzamide from Step A under the
Standard Procedure J. The compound thus obtained was allowed to
react under Standard hydrolysis procedure C (NaOH) to give the
title compound. MS(ES) for C.sub.26H.sub.26FNO.sub.6 [M+H].sup.+:
468.
EXAMPLE 228
[1808]
(2S)-2-Methoxy-3-(4-{3-[4-(4-(3-methoxy-benzoylamino)-phenoxy]-prop-
oxy}-phenyl)-propionic acid 445
[1809] Step A
[1810] N-(4-Hydroxy-phenyl)-3-methoxy-benzamide 446
[1811] The title compound was prepared following the procedure
described in Example 224, Step B with 3-methoxy-benzoyl
chloride.
[1812] Step B
[1813]
(2S)-2-Methoxy-3-(4-{3-[4-(3-methoxy-benzoylamino)-phenoxy]-propoxy-
}-phenyl)-propionic acid
[1814] (2S)-3-[4-(3-Bromo-propoxy)-phenyl]-2-methoxy-propionic acid
ethyl ester from Example 173, Step A was treated with
N-(4-Hydroxy-phenyl-3-met- hoxy-benzamide from Step A under the
Standard Procedure J. The compound thus obtained was allowed to
react under Standard hydrolysis procedure C NaOH) to give the title
compound. MS(ES) for C.sub.27H.sub.29NO.sub.7 [M+H].sup.+: 480.
EXAMPLE 229
[1815]
(2S)-2-Methoxy-3-(4-{3-[4-(3-methyl-benzoylamino)-phenoxy]-propoxy}-
-phenyl)-propionic acid 447
[1816] Step A
[1817] N-(4-Hydroxy-phenyl)-3-methyl-benzamide 448
[1818] The title compound was prepared following the procedure
described in Example 224, Step B with 3-methyl-benzoyl
chloride.
[1819] Step B
[1820]
(2S)-2-Methoxy-3-(4-{3-[4-(3-methyl-benzoylamino-phenoxy]-propoxy}--
phenyl)-propionic acid
[1821] (2S)-3-[4-(3-Bromo-propoxy)-phenyl]-2-methoxy-propionic acid
ethyl ester from Example 173, Step A was treated with
N-(4-Hydroxy-phenyl)-3-me- thyl-benzamide from Step A under the
Standard Procedure J. The compound thus obtained was allowed to
react under Standard hydrolysis procedure C (NaOH) to give the
title compound. MS(ES) for C.sub.27H.sub.29NO.sub.6 [M+H].sup.+:
464.
EXAMPLE 230
[1822]
(2S)-3-(4-{3-[4-(4-Fluoro-benzoylamino)-phenoxy]-propoxy}-phenyl)-2-
-methoxy-propionic acid 449
[1823] Step A
[1824] 4-Fluoro-N-(4-hydroxy-phenyl)-benzamide 450
[1825] The title compound was prepared following the procedure
described in Example 224, Step B with 4-Fluoro benzoyl
chloride.
[1826] Step B
[1827]
(2S)-3-(4-{3-[4-(4-Fluoro-benzoylamino)-phenoxy]-propoxy}-phenyl)-2-
-methoxy propionic acid
[1828] (2S)-3-[4-(3-Bromopropoxy)-phenyl]-2-methoxy-propionic acid
ethyl ester from Example 173, Step A was treated with
4-Fluoro-N-(4-hydroxy-phe- nyl)-benzamide from Step A under the
Standard Procedure J. The compound thus obtained was allowed to
react under Standard hydrolysis procedure C (NaOH) to give the
title compound. MS(ES) for C.sub.26H.sub.26FNO.sub.6 [M+H].sup.+:
468.
EXAMPLE 231
[1829]
(2S)-3-(4-3-[4-(4-Chloro-benzoylamino)-phenoxy]-propoxy}-phenyl)-2--
methoxy-propionic acid 451
[1830] Step A
[1831] 4-Chloro-N-(4-hydroxy-phenyl)-benzamide 452
[1832] The title compound was prepared following the procedure
described in Example 224, Step B with 4-chloro-benzoyl
chloride.
[1833] Step B
[1834]
(2S)-3-(4-{3-[4-(4-Chloro-benzylamino)-phenoxy]-propoxy}-phenyl)-2--
methoxy-propionic acid
[1835] (2S)-3-[4-(3-Bromo-propoxy)-phenyl]-2-methoxy-propionic acid
ethyl ester from Example 173, Step A was treated with
4-chloro-N-(4-hydroxyphen- yl)benzamide from Step A under the
Standard Procedure J. The compound thus obtained was allowed to
react under Standard hydrolysis procedure C (NaOH) to give the
title compound. MS(ES) for C.sub.26H.sub.26ClNO.sub.6 [M+H].sup.+:
484.
EXAMPLE 232
[1836]
(2S)-2-Methoxy-3-(4-{3-[4-(4-methoxy-benzoylamino)-phenoxy]-propoxy-
}-phenyl)-propionic acid 453
[1837] Step A
[1838] N-(4-Hydroxy-phenyl)-4-methoxy-benzamide 454
[1839] The title compound was prepared following the procedure
described in Example 224, Step B with 4-methoxy-benzoyl
chloride.
[1840] Step B
[1841]
(2S)-2-Methoxy-3-(4-{3-[4-(4-methoxy-benzoylamino)-phenoxy]-propoxy-
}-phenyl)-propionic acid
[1842] (2S)-3-[4-(3-Bromo-propoxy)-phenyl]-2-methoxy-propionic acid
ethyl ester from Example 173, Step A was treated with
4-methoxy-N-4-hydroxy-phe- nyl)benzamide from Step A under the
Standard Procedure J. The compound thus obtained was allowed to
react under Standard hydrolysis procedure C (NaOH) to give the
title compound. MS(ES) for C.sub.27H.sub.29NO.sub.7 [M+H].sup.+:
480.
EXAMPLE 233
[1843]
(2S)-2-Methoxy-3-{4-[3-(4-phenylacetylamino-phenoxy)-propoxy]-pheny-
l}-propionic acid 455
[1844] Step A
[1845] N-(4-Hydroxy-phenyl)-2-phenyl-acetamide 456
[1846] The title compound was prepared following the procedure
described in Example 224, Step B with Phenyl-acetyl chloride.
[1847] Step B
[1848]
(2S)-2-Methoxy-3-{4-[3-(4-phenylacetylamino-phenoxy)-propoxy]-pheny-
l}-propionic acid
[1849] (2S)-3-[4-(3-Bromo-propoxy)-phenyl]-2-methoxy-propionic acid
ethyl ester from Example 173, Step A was treated with
N-(4-Hydroxy-phenyl)-2-ph- enyl-acetamide from Step A under the
Standard Procedure J. The compound thus obtained was allowed to
react under Standard hydrolysis procedure C (NaOH) to give the
title compound. MS(ES) for C.sub.27H.sub.29NO.sub.6 [M+H].sup.+:
484.
EXAMPLE 234
[1850]
(2S)-3-(4-{3-[4-(2-Chloro-benzoyl)-phenoxy]-propoxy}-phenyl)-2-meth-
oxy-propionic acid 457
[1851] Step A
[1852] 4-Tributylstannanyl-phenol linked to Wang's resin 458
[1853] p-Iodophenol linked to Wang's resin from Example 211, Step
A, was suspended in toluene and bis-tributyltin was added (5 eq).
The mixture reaction was stirred at 100.degree. C. overnight. Then
filtered through and the resin was washed with
CH.sub.2Cl.sub.2/MeOH/Hexane/MeOH/CH.sub.2C- l.sub.2 to give the
compound.
[1854] Step B
[1855] (2-Chloro-phenyl)-(4-hydroxy-phenyl)-methanone 459
[1856] 4-Tributylstannanyl-phenol linked to Wang's resin from Step
A (1 eq), Pd.sub.2(dba).sub.3 (0.3 eq) and K.sub.2CO.sub.3 (70 mg)
were suspended in THF/Diisopropilmethylamine. To this mixture
2-chloro-benzoyl chloride was added and stirred for 2 hours. The
suspension was filtered and the resin washed with
MeOH/CH.sub.2Cl.sub.2/DMF, then HCl diluted/dioxane and
Na.sub.2CO.sub.3 5%(dioxane) and DMF/MeOH/CH.sub.2Cl.sub.2 Once the
resin was dried TFA 95% and CH.sub.2Cl.sub.2 were added and the
mixture stirred at room temperature for 30 min. The resin was
filtered and washed with MeOH/CH.sub.2Cl.sub.2. The solvents were
collected and concentrated to dryness to give the title
product.
[1857] Step C
[1858]
(2S)-3-(4-{3-[4-(2-Chloro-benzoyl)-phenoxy]-propoxy}-phenyl)-2-meth-
oxy-propionic acid
[1859] (2S)-3-[4-(3-Bromo-propoxy)-phenyl]-2-methoxy-propionic acid
ethyl ester from Example 173, Step A was treated with
(2-Chloro-phenyl)-(4-hydr- oxy-phenyl)-methanone from Step B under
the Standard Procedure J. The compound thus obtained was allowed to
react under Standard hydrolysis procedure C (NaOH) to give the
title compound. MS(ES) for C.sub.26H.sub.25ClO.sub.6
[M+NH.sub.4].sup.+: 491, [M+H].sup.+: 469.
EXAMPLE 235
[1860]
(2S)-2-Methoxy-3-(4-{3-[4-(naphthalene-1-carbonyl)-phenoxy]-propoxy-
}-phenyl) propionic acid 460
[1861] Step A
[1862] (4-Hydroxy-phenyl)-naphthalen-1-yl-methanone 461
[1863] The title compound was prepared following the procedure
described in Example 234, Step B with naphthalene-1-carbonyl
chloride.
[1864] Step B
[1865] (2S)-2-Met
oxy-1-3-(4-4-(naphthalene-1-carbonyl)-phenoxy]-propoxy}--
phenyl)-propionic acid
[1866] (2S)-3-[4-(3-Bromo-propoxy)-phenyl]-2-methoxy-propionic acid
ethyl ester from Example 173, Step A wag treated with
(4-Hydroxy-phenyl)-naphth- alen-1-yl-methanone from Step A under
the Standard Procedure I. The compound thus obtained was allowed to
react under Standard hydrolysis procedure C (NaOH) to give the
title compound. MS(ES) for C.sub.30H.sub.28O.sub.6
[M+NH.sub.4].sup.+: 507, [M+H]+485.
EXAMPLE 236
[1867]
(2S)-3-(4-{3-[4-(3-Fluoro-benzoyl)-phenoxy]-propoxy}-phenyl-2-metho-
xy-propionic acid 462
[1868] Step A
[1869] (3-Fluoro-phenyl)-(4-hydroxy-phenyl)-methanone 463
[1870] The title compound was prepared following the procedure
described in Example 234, Step B with 3-Fluoro-benzoyl
chloride.
[1871] Step B
[1872]
(2S)-3-(4-{3-[4-(3-Fluoro-benzoyl)-phenoxy]-propoxy}-phenyl)-2-meth-
oxy-propionic acid
[1873] (2S)-3-[4-(3-Bromo-propoxy)-phenyl]-2-methoxy-propionic acid
ethyl ester from Example 173, Step A was treated with
(3-Fluoro-phenyl)-(4-hydr- oxy-phenyl)-methanone from Step A under
the Standard Procedure J. The compound thus obtained was allowed to
react under Standard hydrolysis procedure C (NaOH) to give the
title compound. MS(ES) for C.sub.26H.sub.25FO.sub.6 [M+H].sup.+:
453.5.
EXAMPLE 237
[1874]
(2S)-2-Methoxy-3-(4-{3-[4-(3-methoxy-benzoyl)-phenoxy]-propoxy}-phe-
nyl)-propionic acid 464
[1875] Step A
[1876] (4-Hydroxy-phenyl)-(3-methoxy-phenyl)-methanone 465
[1877] The title compound was prepared following the procedure
described in Example 234, Step B with 3-methoxy-benzoyl
chloride.
[1878] Step B
[1879]
(2S)-2-Methoxy-3-(4-{3-[4-(3-methoxy-benzoyl)-phenoxy]-propoxy}-phe-
nyl)-propionic acid
[1880] (2S)-3-[4-(3-Bromo-propoxy)-phenyl]-2-methoxy-propionic acid
ethyl ester from Example 173, Step A was treated with
(4-Hydroxy-phenyl)-(3-met- hoxy-phenyl)-methanone from Step A under
the Standard Procedure J. The compound thus obtained was allowed to
react under Standard hydrolysis procedure C (NaOH) to give the
title compound. MS(ES) for C.sub.27H.sub.28O.sub.7 [M+H].sup.+:
465.
EXAMPLE 238
[1881]
(2S)-2-Methoxy-3-(4-{3-[4-(naphthalen-2-carbonyl)-phenoxy]-propoxy}-
-phenyl)-propionic acid 466
[1882] Step A
[1883] (4-Hydroxy-phenyl)-naphthalen-2-yl-methanone 467
[1884] The title compound was prepared following the procedure
described in Example 234, Step B with naphtalene-2-carbonyl
chloride.
[1885] Step B
[1886]
(2S)-2-Methoxy-3-(4-{3-[4-(naphthalene-2-carbonyl)-phenoxy]-propoxy-
}-phenyl)-propionic acid
[1887] (2S)-3-[4-(3-Bromo-propoxy)-phenyl]-2-methoxy-propionic acid
ethyl ester from Example 173, Step A was treated with
(4-Hydroxy-phenyl)-naphth- alen-2-yl-methanone from Step A under
the Standard Procedure 3. The compound thus obtained was allowed to
react under Standard hydrolysis procedure C (NaOH) to give the
title compound. MS (ES) for C.sub.30H.sub.28O.sub.6 [M+H].sup.+:
485.
EXAMPLE 239
[1888]
(2)-2-Methoxy-3-(4-{3-[3-(4-methyl-benzoyl)-phenoxy]-propoxy}-pheny-
l)-propionic acid 468
[1889] Step A
[1890] (4-Hydroxy-phenyl)-p-tolyl-methanone 469
[1891] The title compound was prepared following the procedure
described in Example 234, Step B with 4-methyl-benzoyl
chloride.
[1892] Step B
[1893]
(2S)-2-Methoxy-3-(4-{3-[4-(4-methyl-benzoyl)-phenoxy]-propoxy}-phen-
yl)-propionic acid
[1894] (2S)-3-[4-(3-Bromo-propoxy)-phenyl]-2-methoxy-propionic acid
ethyl ester from Example 173, Step A was treated with
(4-Hydroxy-phenyl)-p-toly- l-methanone from Step A under the
Standard Procedure J. The compound thus obtained was allowed to
react under Standard hydrolysis procedure C (NaOH) to give the
title compound. MS(ES) for C.sub.27H.sub.28O.sub.6
[M+NH.sub.4].sup.+: 471 [M+H].sup.+: 449.
EXAMPLE 240
[1895]
(2S)-3-(4-{3-[4-(2,2-Dimethyl-propionyl)-phenoxy]-propoxy}-phenyl)--
2-methoxy-propionic acid 470
[1896] Step A
[1897] 1-(4-Hydroxy-phenyl)-2,2-dimethyl-propan-1-one 471
[1898] The title compound was prepared following the procedure
described in Example 234, Step B with 2,2-Dimethyl-propionyl
chloride.
[1899] Step B
[1900]
(2S)-3-(4-{3-[4-(2,2-Dimethyl-propionyl)-phenoxy]-propoxy}-phenyl)--
2-methoxy-propionic acid
[1901] (2S)-3-[4-(3-Bromo-propoxy)-phenyl]-2-methoxy-propionic acid
ethyl ester from Example 173, Step A was treated with
1-(4-Hydroxyphenyl)-2,2-d- imethyl-propan-1-one from Step A under
the Standard Procedure J. The compound thus obtained was allowed to
react under Standard hydrolysis procedure C (NaOH) to give the
title compound. MS(ES) for C.sub.24H.sub.30O.sub.6
[M+NH.sub.4].sup.+: 437 [M+H].sup.+: 415.
EXAMPLE 241
[1902]
(2S)-3-{4-[3-(4-Isobutyryl-phenoxy)-propoxy]-phenyl}-2-methoxy-prop-
ionic acid 472
[1903] Step A
[1904] 1-(4-Hydroxy-phenyl)-2-methyl-propan-1-one 473
[1905] The title compound was prepared following the procedure
described in Example 234, Step B with Isobutyryl chloride.
[1906] Step B
[1907]
(2S)-3-{4-[3-(4-Isobutyryl-phenoxy)-propoxy]-phenyl}-2-methoxy-prop-
ionic acid
[1908] (2S)-3-[4-(3-Bromo-propoxy)-phenyl]-2-methoxy-propionic acid
ethyl ester from Example 173, Step A was treated with
1-(4-Hydroxy-phenyl)-2-me- thyl-propan-1-one from Step A under the
Standard Procedure J. The compound thus obtained was allowed to
react under Standard hydrolysis procedure C (NaOH) to give the
title compound. MS(ES) for C.sub.23H.sub.28O.sub.6
[M+NH.sub.4].sup.+: 423 [M+H].sup.+: 401.
EXAMPLE 242
[1909]
(2S)-2-Methoxy-3-(4-{3-[4-(3-phenyl-propionyl)-phenoxy]-propoxy}-ph-
enyl}-phenyl)-propionic acid 474
[1910] Step A
[1911] 1-(4-Hydroxy-phenyl)-3-phenyl-propan-1-one 475
[1912] The title compound was prepared following the procedure
described in Example 234, Step B with 3-Phenyl-propionyl
chloride.
[1913] Step B
[1914]
(2S)-2-Methoxy-3-(4-{3-[4-(3-phenyl-propionyl)-phenoxy]-propoxy}-ph-
enyl)-propionic acid
[1915] (2S)-3-[4-(3-Bromo-propoxy)-phenyl]-2-methoxy-propionic acid
ethyl ester from Example 173, Step A was treated with
1-(4-Hydroxy-phenyl)-3-ph- enyl-propan-1-one from Step A under the
Standard Procedure 3. The compound thus obtained was allowed to
react under Standard hydrolysis procedure C (NaOH) to give the
title compound. MS(ES) for C.sub.28H.sub.30O.sub.6
[M+NH.sub.4].sup.+: 485 [M+H].sup.+: 463.
EXAMPLE 243
[1916]
3-{4-[3-(Biphenyl-4-yloxy)-propoxy]-2-fluoro-phenyl}-2-methoxy-prop-
ionic acid 476
[1917] Step A
[1918] 2-Fluoro-4-hydroxy-benzaldehyde 477
[1919] 2-Fluoro-4-methoxy-benzaldehyde (1 g, 6.49 mmol) was added
to a suspension of anhydrous potassium iodide (2.15 g, 13 mmol) and
aluminum trichloride (1.04 g, 7.8 mmol) in anhydrous toluene (10
mL), and the mixture was stirred at 40.degree. C. for 3 hours.
Aluminum trichloride (2.15 g, 13 mmol) and anhydrous potassium
iodide (0.86 g, 6.49 mmol) were added, and the mixture was stirred
for 3 hours. The mixture was diluted with water (10 mL) and
extracted with ethyl acetate (5.times.20 mL). The combined organic
layers were dried (MgSO.sub.4), filtered, and concentrated under
vacuum. The residue was purified by silica gel chromatography
(silica gel, hexanes/ethyl acetate 4:1) to give
2-fluoro-4-hydroxy-benzaldehyde as a white solid (260 mg, 29%).
.sup.1H NMR (200 MK, Acetone-d.sub.4): .delta. 10.08 (s, 1H), 9.77
(b, 1H), 7.69 (t, 1H, J=8.4), 6.78 (dd, 1H, J=8.8, 2.6), 6.65 (dd,
1H, J=12.5, 2.2)ppm.
[1920] Step B
[1921] 4-[3-(Biphenyl-4-yloxy)-propoxy]-2-fluoro-benzaldehyde
478
[1922] Potassium tert-butoxide (0.217 g, 1.93 mmol) was added to a
solution of 2-fluoro-4-hydroxy-benzaldehyde (0.246 g, 1.76 mmol) in
anhydrous DMF (5 mL) at 0.degree. C., and the mixture was stirred
for 30 min. 4-(3-Bromo-propoxy)-biphenyl (0.564 g, 1.93 mmol,
Example 132, Step D) was added, and the mixture stirred at room
temperature for 24 hours. The reaction mixture was diluted with
water and extracted with EtOAc (5.times.15 mL). The combined
organic layers were dried (MgSO.sub.4), filtered, and concentrated
under vacuum. The residue was purified by silica gel chromatography
(silica gel, hexanes/ethyl acetate 4:1) to give
4-[3-(biphenyl-4-yloxy)-propoxy]-2-fluoro-benzaldehyde as a white
solid (540 mg, 88%). .sup.1H NMR (200 MHz, CDCl.sub.3): .delta.
10.19 (s, 1H), 7.80 (t, 1H, J=8.4); 7.55-7.48 (m, 4H); 7.42-7.27
(m, 3H); 6.99-6.93 (m, 2H); 6.78 (dd, 1H, J=8.8, 2.6); 6.64 (dd,
1H, J=12.4, 2.2); 4.27-4.15 (m, 4H); 2.30 (qn, 2H, J=5.9)ppm.
[1923] Step C
[1924]
3-{4-[3-(Biphenyl-4-yloxy)-propoxy]-2-fluoro-phenyl}-3-hydroxy-3-me-
thoxy-propionic acid methyl ester 479
[1925] A solution of
4-[3-(biphenyl-4-yloxy)-propoxy]-2-fluoro-benzaldehyd- e (0.320 g,
0.91 mmol) and methyl methoxyacetate (0.099 mL, 1 mmol) in THF (0
mL) at -78.degree. C. was added dropwise to sodium
bis(trimethylsilyl)amide (1 mL, 1 mmol, 1N in THF) at -78.degree.
C. The reaction mixture was stirred for 3 hours, quenched with 1N
HCl (1 mL), and allowed to warm to room temperature. The mixture
was diluted with water (10 mL) and extracted with ethyl acetate
(3.times.30 mL). The combined organic layers were dried
(MgSO.sub.4), filtered, and concentrated under vacuum. The residue
was purified by silica gel chromatography (silica gel,
hexanes/ethyl acetate 2:1) to give a 1:1 diastereomeric mixture of
3-{4-[3-biphenyl-4-yloxy)-propoxy]-2-fluoro-phe-
nyl}-3-hydroxy-2-methoxy-propionic acid methyl ester as a white
solid (250 mg, 60%). .sup.1H NMR (200 MHz, CDCl.sub.3): 7.55-7.47
(m, 4H), 7.42-7.23 (m, 4H), 6.95 (d, 2H, J=8.4), 6.73-6.66 (m, 1H),
6.59 (dd, 1H, J=12.4, 2.6), 5.19 (dd, 1H, J=15.4, 4.8), 4.18-4.04
(m, 4H), 3.93 (d, 1H, J=5.1), 3.68 and 3.63 (2 s, 3H), 3.39 and
3.37 (2 s, 3H), 3.12 (b, 1H), 2.24 (qn, 2H, J=6.2)ppm.
[1926] Step D
[1927]
3-{4-[3-(Biphenyl-4-yloxy)-propoxy]-2-fluoro-phenyl}-2-methoxy-prop-
ionic acid methyl ester 480
[1928] Trifluoroacetic anhydride (0.043 mL, 0.37 mmol) and pyridine
(0.074 mL, 0.93 mmol) were added to a solution of
3-{4-[3-biphenyl-4-yloxy)-prop-
oxy]-2-fluoro-phenyl}-3-hydroxy-2-methoxy-propionic acid methyl
ester (0.142 g, 0.31 mmol) in methylene chloride (1 mL) at
0.degree. C. The resulting mixture was stirred for 4 hours at room
temperature and was concentrated under vacuum. The residue was
dissolved in ethyl acetate (50 mL) and 10% palladium on carbon
(0.064 g) was added to the solution. The mixture was stirred under
hydrogen pressure (5 atm) for 16 hours. The mixture was filtered
through celite and concentrated under vacuum. The residue was
purified by silica gel chromatography (silica gel, hexanes/ethyl
acetate 4:1) to give 3-{4-[3-biphenyl-4-yloxy)-propoxy]-2-f-
luoro-phenyl}-2-methoxy-propionic acid methyl ester as a white
solid (30 mg, 22%). .sup.1H NMR (200 MHz, CDCl.sub.3): 7.60-7.50
(m, 4H); 7.46-7.27 (m, 3H); 7.18-7.09 (m, 1H); 7.03-6.96 (m, 2H);
6.70-6.61 (m, 2H); 4.17 (dt, 4H, J=9.1, 6.2); 4.00 (dd, 1H, J=7.3,
5.9); 3.74 (s, 3H); 3.37 (s, 3H); 3.13-2.93 (m, 2H); 2.28 (qn, 2H,
J=6.2).
[1929] Step E
[1930]
3-{4-[3-(Biphenyl-4-yloxy)-propoxy]-2-fluoro-phenyl}-2-methoxy-prop-
ionic acid
[1931] 1N aqueous lithium hydroxide solution (1.37 mL) was added to
a solution of
3-{4-[3-(biphenyl-4-yloxy)-propoxy]-2-fluoro-phenyl}-2-methox-
y-propionic acid methyl ester (0.075 g, 0.17 mmol) in THF (2 mL) at
room temperature. The reaction mixture was stirred overnight,
diluted with water (10 mL), and extracted with diethyl ether
(3.times.20 mL). The aqueous layer was acidified with 1N HCl to pH
1 and extracted with ethyl acetate (3.times.25 mL). The combined
organic layers were dried (MgSO.sub.4), filtered, and concentrated
to give 3-{4-[3-(biphenyl-4-ylox-
y)-propoxy]-2-fluoro-phenyl}-2-methoxy-propionic acid as a white
solid (60 mg, 83%). .sup.1H-NMR (200, CDCl.sub.3): 7.56-7.29 (m,
7H), 7.18-7.09 (m, 1H), 6.98 (d, 2H, J=8.6), 6.66-6.60 (m, 2H),
4.17 (dt, 4H, J=8.9, 5.9), 4.03 (dd, 1H, J=6.7, 4.8), 3.40 (s, 3H),
3.23-3.14 (m, 1H), 2.97 (dd, 1H, J=14.0, 6.7), 2.26 (q, 2H,
J=5.9)ppm.
EXAMPLE 244
[1932] 2-phenoxy-3-[4-(4-phenoxy-phenoxy)-propoxyphenyl]propanoic
acid 481
[1933] Step A
[1934] 1-(3-bromopropoxy)-4-phenoxybenzene 482
[1935] The title compound was prepared from 4-phenoxyphenol
following the same procedure as in Example 132, Step D. .sup.1H-NMR
(200.15 MHz, CDCl.sub.3): .delta. 7.35-7.25 (m, 2H), 7.09-6.87 (m,
7H), 4.10 (t, 2H, J=5.9), 3.62 (t, 2H, J=6.1), 2.55-2.21 (m,
2H)ppm.
[1936] Step B
[1937] 4-Benzyloxyphenyl-2-hydroxypropanoic acid methyl ester
483
[1938] A solution of DL-4-hydroxyphenyllactic acid (0.5 g, 2.74
mmol) was stirred over night in MeOH/HCl saturated solution. The
reaction was concentrated to dryness and the crude product (0.545
g, 2.7 mmol) was treated with K.sub.2CO.sub.3 (3 eq.) and benzyl
bromide (0.507 g, 2.97 mmol) in acetonitrile (20 ml) and refluxed
overnight. The crude reaction was filtered off and concentrated to
produce a crude product. The residue was purified by chromatography
(silca-gel, hexanes/Ethyl acetate (3:1) to give a white oil
(97.degree.). .sup.1H-NMR (200.15 MHz, CDCl.sub.3): .delta.
7.43-7.35 (m, 5H), 7.14 (d, 2H, J=8.59), 6.92 (d, 2H, J=8.59), 5.04
(s, 2H), 4.42 (dd, 1H, J=10.7, 6.1), 2.97 (ddd, 2H, J=4.5, 13.9,
31.1), 2.73 (d, 1H, J=6.1).
[1939] Step C
[1940] 4-Benzyloxyphenyl-2-(4-chlorophenoxy)propanoic acid methyl
ester 484
[1941] A solution of triphenylphosphine-(0.1 g, 0.38 mmol) in 5 ml
of dry THF was treated at 0.degree. C. with DEAD (0.066 g, 0.38
mmol) and stirred over 30 min. Then a solution of
4-Benzyloxyphenyl-2-hydroxypropan- oic acid methyl ester (0.1 g,
0.35 mmol) and p-chlorophenol (0.048 g, 0.38 mmol) in 2 ml of THF
was added to the solution and the mixture reaction was stirred at
room temperature overnight. The mixture was concentrated to dryness
and chromatographed in silica gel (hexanes/Ethyl acetate 3:1) to
give 0.082 g of product (60%). .sup.1H-NMR (200.15 MHz,
CDCl.sub.3): 37.46-7.31 (m, 5H), 7.28-7.13 (m, 4H), 6.93 (d, 2H,
J=8.8), 6.75 (d, 2H, J=8.8), 5.04 (s, 2H), 4.73 (t, 1H, J=6.1),
3.71 s (s, 3H), 3.18 (d, 2H, J=6.4).
[1942] Step D
[1943] 4-Hydroxyphenyl-2-phenoxypropanoic acid methyl ester 485
[1944] A solution of 4-Benzyloxyphenyl-Z-(4-chlorophenoxy)propanoic
acid methyl ester in ethanol with 10% Pd/C (5 wt %) was stirred
under hydrogen atmosphere (1 tm) over 2 hours. The catalyst was
removed via filtration through a pad of celite and the filtrated
concentrated in vacuo to produce the title compound (90%).
.sup.1H-NMR (200.15 MHz, CDCl.sub.3): .delta. 7.25-7.14 (m, 4H),
7.94-7.73 (m, 4H), 4.81-4.69 (m, 1H), 3.70 (s, 3H), 3.16 (d, 2H,
J=4.1).
[1945] Step E
[1946] 2-phenoxy-3-[4-(4-phenoxy phenoxy)propoxyphenyl]propanoic
acid methyl ester 486
[1947] A mixture of 3-(4-hydroxyphenyl)-2-phenoxypropanoic acid
methyl ester (0.055 g, 0.18 mmol) with
1-(3-bromopropoxy)-4-phenoxybenzene (Step A) (0.055 g, 0.18 mmol)
and potassium tert-butoxide (0.020 g, 0.18 mmol) were stirred in
DMF (5 mL) overnight. The mixture reaction concentrated in vacuo
with toluene (2 times), reconstituted in Ethyl acetate and washed
with water (3 times) and brine, dryed (Na.sub.2SO.sub.4) and
concentrated to afford a crude product that was purified by
chromatographied in silicagel (hexanes/Ethyl acetate, 3:1) to give
0.022 g of the title compound (23%). .sup.1H-NMR (200.15 MHz,
CDCl.sub.3): .delta. 7.34-7.15 (m, 6H), 7.07-6.71 (m, 12H),
4.80-4.68 (m, 1H), 4.13 (t, 4H, J=15.1), 3.71 (s, 3H), 3.20-3.15
(m, 2H), 2.30-2.18 (q, 2H).
[1948] Step F
[1949] 2-phenoxy-3-[4-(4-phenoxy phenoxy)propoxphenyl]propanoic
acid
[1950] The title compound was prepared from
2-phenoxy-3-[4-(4-phenoxy phenoxy)-propoxyphenyl]propanoic acid
methyl ester (0.022 g, 0.04 mmol). That was stirred with an excess
of LiOH 3N (5 eq.) in THF (3 ml) overnight. The solution was
acidulate with HCl 1N (to pH 1-2) and extracted with ethyl acetate.
The organic layer was dried (Na.sub.2SO.sub.4) and concentrated
under vacuum to produce an oily solid (80%. .sup.1H-NMR (200.15
MHz, CDCl.sub.3): .delta. 7.33-7.16 (m, 6H), 7.03-6.70 (m, 12H),
4.84-4.71 (m, 1H), 4.13 (t, 4H, J=6.1), 3.24-3.19 (m, 2H)ppm.
EXAMPLE 245
[1951]
(2S,2')-3-(4-{3-[4-(2'-Carboxy-2'-methoxy-ethyl)-phenoxy]-propoxy}--
phenyl)-2-methoxy-propionic acid 487
[1952] A mixture of (2S)-3-[4-(3-hydroxy-phenyl]-2-methoxypropionic
acid ethyl ester (2 eq), and propylene glycol (1.3 eq) were allowed
to react under the Standard Mitsounobu coupling conditions B
(DIAD/Toluene), and the resulting product of this reaction was
treated following the Standard hydrolysis conditions C to give the
title compound. MS(ES) for C.sub.23H.sub.28O.sub.8
[M+NH.sub.4].sup.+: 450, [M+H].sup.+: 433.
EXAMPLE 246
[1953] Synthesis of .alpha.-Methoxycinnamate Intermediate, ethyl
(2S)-2-methoxy-3-(4-hydorxphenyl)propanoate (e) 488
[1954] Step 1a: methyl
3-hydroxy-2-methoxy-3-[4-phenylmethoxy)-phenyl]prop- anoate (a)
[1955] Sodium bis-(trimethylsilyl)amide (440 mL 0.44 mol 1.0 M in
THF) was cooled to -70.degree. C. under a nitrogen atmosphere. A
solution of 4-benzyloxybenzaldehyde (85 g, 0.4 mol) and methyl
methoxyacetate (52 g, 0.5 mol) in THF (0.5 L) was added dropwise at
-70.degree. C. over 2 hours, and the mixture was stirred for an
hour. A solution of concentrated HCl (85 mL) and water (85 mL) was
added at -70.degree. C. The resulting solution was allowed to warm
to ambient temperature and was extracted with MTBE (2.times.0.5 L).
The combined extracts were washed with brine (0.5 L), dried
(MgSO.sub.4), filtered, and concentrated under to give 133 g of a
red oil.
[1956] Step 1b and Step 1c: methyl
3-(4-hydroxyphenyl)-2-methoxypropanoate (b)
[1957] Methyl
3-hydroxy-2-methoxy-3-[(phenylmethoxy)-phenyl]propanoate (133 g,
crude from above) was dissolved in CH.sub.2Cl.sub.2 (700 mL), and
pyridine (129 mL, 1.6 mol) was added. The resulting solution was
cooled in a water bath and trifluoroacetic anhydride (85 mL, 0.6
mol) was added dropwise under nitrogen. The bath was removed, and
the mixture was stirred at ambient temperature for 16 hours. The
solution was cooled to 0.degree. C. and concentrated HCl (150 mL)
in water (1 L) was added dropwise. The organic layer was separated
and concentrated, and ethyl acetate (0.5 L) was added. The
resulting solution was treated with hydrogen gas under 50 psi in
the presence of 5% Pd--C (80 g, 50% water wet) at ambient
temperature for 16 hours. The catalyst was filtered, and the
filtrate was concentrated under vacuum to give 122 g oil.
.sup.1H-NMR (CDCl.sub.3): 7.1 (2H, d); 6.7 (d, 2H); 5.4 (s, 1H);
4.0 (m, 1H); 3.7 (s, 3H); 3.4 (s, 3H); 3.0 (m, 1H). MS (ES)=209.2
(M-1).
[1958] Step 1d: 3-(4-hydroxphenyl)-2-methoxypropanoic acid (c)
[1959] Methyl 3-(4-hydroxyphenyl)-2-methoxypropanoate (132 g, 0.631
mol) was dissolved in methanol (700 mL) and 5N sodium hydroxide
(631 mL, 3.16 mol) was added dropwise at ambient temperature. The
solution was stirred for 16 hours at ambient temperature. The
methanol was removed under vacuum, and water (500 mL) was added.
The mixture was extracted with MTBE (2.times.500 mL). The aqueous
solution was brought to pH=1 with concentrated HCl and then
extracted with MTBE (2.times.500 mL). The organic extracts were
dried (MgSO.sub.4), filtered, and concentrated under vacuum to give
the racemic acid as an oil (110 g) which was crystallized upon
standing. .sup.1H-NMR (DMSO): 7.0 (d, 2H); 6.6 (d, 2H); 4.0 (m,
1H); 2.8 (m, 2H). MS (ES)=195.1-1).
[1960] Step 2: (2S)-3-(4-hydroxyphenyl)-2-methoxypropanoic acid
(d)
[1961] Cinchonidine salt of
(2S)-3-(4-hydroxyphenyl)-2-methoxypropanoic acid
[1962] A slurry consisting of
3-(4-hydroxyphenyl)-2-methoxypropanoic acid (21.21 g, 0.1081 mol),
(-)-cinchonidine (31.83 g, 0.1081 mol), and THF (424 mL) was heated
briefly at reflux to give a red-brown solution. The mixture was
cooled to ambient temperature and stirred for 3 days. The
resulting-slurry was cooled to 0.degree. C. for 4 hours and
filtered to give about 17.06 g of the cinchonidine salt (71.2% ee
by chiral HPLC). The cinchonidine salt was slurried in THF, heated
to reflux for 1 hour, and cooled to ambient temperature overnight.
The mixture was cooled to 0.degree. C. for 2 hours and filtered to
give about 14.87 g of the cinchonidine salt (83.0% ee by chiral
HPLC). The cinchonidine salt was slurried again in THF, and heated
to reflux for 1 hour, and cooled to ambient temperature. The
mixture was cooled to 0.degree. C. for 2 hours and filtered to give
about 12.87 g (24%) of the cinchonidine salt of
(2S)-3-(4-hydroxyphenyl)-2-methoxypropanoic acid (91.4% ee by
chiral HPLC).
[1963] (2S)-3-(4-hydroxyphenyl)-2-methoxypropanoic acid
[1964] The cinchonidine salt of
(2S)-3-(4-hydroxyphenyl)-2-methoxypropanoi- c acid (73.59 g, 0.15
mol) (98.1% ee by chiral HPLC) was suspended in 1N HCl solution
(750 mL) and extracted with methyl tert butyl ether (3.times.200
mL). The combined extracts were dried (Na.sub.2SO.sub.4) and
concentrated to give about 24.12 g (82%) of
(2S)-3-(4-hydroxyphenyl)-2-me- thoxypropanoic acid (96.7% ee by
chiral HPLC). .sup.1H NMR (DMSO-d.sub.6): .delta. 2.72-2.89 (m,
2H), 3.21 (s, 3H), 3.8-3.87 (m, 1H), 6.64-6.67 (d, 2H), 6.97-7.02
(d, 2H), 9.15 (s, broad, 1H), 12.62 (s, broad, 1H). MS (ES.sup.+):
m/z 219.0 ([M+Na].sup.+). MS (ES.sup.-) m/z 195.1 ([M-H].sup.-).
[.alpha.].sub.D=-2.2.degree. (c=1, MeOH).
[1965] Step 3: ethyl (2S)-2-methoxy-3-(4-hydroxyphenyl)propanoate
(e)
[1966] A solution of (2S)-3-(4-hydroxyphenyl)-2-methoxypropanoic
acid (35 g) in 140 ml of ethanol was mixed with 5.66 ml of
concentrated sulfuric acid and stirred at room temperature until
complete as indicated by HPLC. The ethanol was removed via vacuum
distillation (55.degree. C./28"Hg) and 110 ml of water was added.
The pH was adjusted to about 7 to 8 with sodium bicarbonate, and
the mixture was extracted with add 50 ml ethyl acetate (3.times.50
ml). The organic layers were combined, washed with 50 ml 20% NaCl
solution, dried with 15 g of magnesium sulfate, and concentrate
product to afford ethyl (2S)-2-methoxy-3-(4-hydorxyphenyl)pro-
panoate as an oil. .sup.1H-NMR (CDCl.sub.3): 7.1 (d, 2H); 6.7 (d,
2H); 4.2 (m, 2H); 3.9 (m, 1H); 3.6 (s, 3H); 2.95 (m, 2H); 1.25 (t,
3H). MS (ES): 223.2 (M-1).
EXAMPLE 247
[1967] Synthesis of
(2S)-2-methoxy-3-{4-[3-(4-phenoxy-phenoxy)-propoxy]phe-
nyl}propanoic acid 489 490
[1968] Step 1: 1-bromo-3-(phenoxyphenyl)propane (a)
[1969] To a 22 L flask was added 4-phenoxyphenol (900 g),
1,3-dibrompropane (5858 g), powered potassium carbonate (1335 g),
and methyl ethyl ketone (9 L). The mixture was stirred for 30
minutes at 22.degree. C. The off-white slurry was heated to a
gentle reflux (83.degree. C.) and held at that temperature for 16
hours. The off white slurry was cooled to 25.degree. C. and vacuum
filtered, washing the cake of inorganic salts with methyl ethyl
ketone (4 L). The filtrate was concentrated on a rotary evaporator
while increasing the temperature to 90.degree. C. under house
vacuum. After the condensation had stopped, the oil was held at
90.degree. C. under vacuum for an additional two hours to ensure
the remaining 1,3-dibrompropane below 8% by GC analysis. The
residue was dissolved in 3 L of methyl alcohol, and the white
slurry was cooled slowly to about 0-5.degree. C. and held at that
temperature overnight. The product was filtered, washed with cold
methyl alcohol (6 L), and dried at 30.degree. C. for about 20 hours
to afford about 1234 g of compound (a) in 84% yield (99.4%-pure by
GC). .sup.1H-NMR (CDCl.sub.3): 7.3 (2H, m), 7.1 (2H, m), 7.0 (2H,
m), 6.9 (2H, m), 4.1 (2H, m); 3.6 (2H, m); 2.3 (2H, m).
[1970] Step 2: ethyl
(2S)-2-methoxy-3-{4-[3-(4-phenoxy-phenoxy)-propoxy]ph-
enyl}propanoate (b)
[1971] 1-Bromo-3-(4-phenoxyphenyl)-propane (1337 g), ethyl
(2S)-2-methoxy-3-(4-hydorxyphenyl)propanoate (957 g) and
dimethylformamide (5 L) were charged to a 22 L flask. After a
solution was obtained, powered-potassium carbonate (1770 g) was
added. The mixture was stirred for 16 hours at ambient temperature
and then quenched by adding water (6.5 L) while maintaining
temperature at 20 to 30.degree. C. The aqueous layer was extracted
three times with ethyl acetate (5 L each). The combined organic
layers were washed with water (3.times.4 L) and brine (4 L). The
organic layer was then dried with sodium sulfate (1000 g),
filtered, and washed with ethyl acetate. The filtrate was
concentrated to afford about 1974 g of crude (b). .sup.1H-NMR
(CDCl.sub.3): 7.3 (m, 2H); 72 (d, 2H); 7.0 (m, 1H); 6.95 (m, 4H);
6.9 (d, 2H); 6.85 (d, 2H); 4.2 (m, 2H); 4.15 (m, 4H); 3.9 (t, 1H);
3.39 (s, 3H); 2.99 (m, 2H); 2.25 (m, 2H); 1.25 (m, 3H). MS
(ES)=468.2 (M+NH.sub.4).
[1972] Step 3:
2S-2-methoxy-3-{4-[3-(4-phenoxy-phenoxy)-propoxy]phenyl}pro- panoic
acid, sodium salt (c)
[1973] To a 22 L flask, a solution of compound (b) (987 g) in
ethanol (10 L) was added and stirred, followed by adding 5 N NaOH
(4.4 L) for over 60 minutes at a temperature at 20 to 30.degree. C.
The slurry was stirred for about an hour at ambient temperature and
then cooled to 10-15.degree. C. where the mixture was held at that
temperature for 1 hour and filtered. The solid was washed with
alcohol (8 L) and MTBE (50 L) to afford the compound (c), which can
be further purified by recrystallizing from ethyl acetate:
.sup.1H-NMR (DMSO): 7.35 (m, 2H); 7.1 (m, 3H); 7.0 (m, 4H), 6.9 (d,
2H); 6.8 (d, 2H); 4.1 (m, 4H); 3.4 (t, 1H); 3.1 (s, 3H); 2.8 (dd,
1H); 2.6 (m, 1H); 2.15 (m, 2H). MS (ES): 421.2 (M-1).
[1974] Step 4:
2S-2-methoxy-3-{4-[3-(4-phenoxy-phenoxy)-propoxy]-phenyl}-p-
ropanoic acid (d)
[1975]
2-Methoxy-3-{4-[3-(4-phenoxy-phenoxy)-propoxy]-phenyl}-propionic
acid ethyl ester (b) (12.15 g, 27 mmol) was dissolved in ethanol
(250 ml) at ambient temperature, and 5N NaOH (54 ml, 270 mmol) was
added dropwise. The slurry was stirred at ambient temperature for 2
hours. The mixture was diluted with water (250 ml), and conc. HCl
(33 ml) was added dropwise. The resulting slurry was stirred at
ambient temperature for about 2 hours. The white solid was filtered
and dried under vacuum at 70.degree. C. for 16 hours to afford
about 10.5 g of the compound (d). .sup.1H-NMR (CDCl.sub.3): 7.3 (m,
2H), 7.18 (d, 2H), 7.07 (t, 1H), 6.9 (m, 8H), 4.19 (m, 4H), 4.0 (m,
1H), 3.4 (s, 3H), 3.0 (m, 2H), 2.25 (m, 2H). MS (ES): 421.2
(M-1).
EXAMPLE 248
[1976]
(2S)-(2'RS)-2-Methoxy-{4-[2'-methyl-3-(4-phenoxy-phenoxy)-propoxy]--
phenyl}-propionic acid 491
[1977] A solution of
(2S)-2-Methoxy-3-{4-[2-(4-phenoxy-phenoxy)-propoxy]-p-
henyl}-propionic acid
(4-[2-methylen-3-(4-phenoxy-phenoxy)-propoxy]-phenyl- }-propionic
acid from Example 74, in ethanol was treated with Pd/C and H.sub.2
for over 2 hours at 1 atm. The mixture was filtered through celite
and concentrated to dryness to afford the title compound as a
mixture of isomers. MS (ES) for C.sub.26H.sub.28O.sub.6
[M+NH.sub.4].sup.+: 454.2, [M-H].sup.-: 435.2.
EXAMPLE 249
[1978] 2(S)-3-[4-(3-Benzyloxy-propoxy)-phenyl]-2-methoxypropionic
acid 492
[1979] The title compound was prepared from
(2S)-3-[4-(3-hydroxy-phenyl]-2- -methoxypropionic acid linked to
Wang's Resin (Example 94, Step C) via the Mitsunobu
reaction-cleavage (Standard Procedure G). .sup.1H-NMR (200.15 MHz,
CDCl.sub.3): 7.4-7.2 (m, 5H), 7.14 (d, 2H, J=8.6), 6.82 (d, 2H,
J=8.6), 4.52 (s, 2H), 4.06 (t, 2H, J=6.2), 3.97 (dd, 1H, J=7.2,
4.6), 3.65 (t, 2H, J=6.2), 3.39 (s, 3H), 3.09 (dd, 1H, J=14.4,
4.4), 2.95 (dd, 1H, J=14.4, 7.2), 2.07 (qn, 2H, J=6.2).
EXAMPLE 250
[1980] (2S)-3-[4-(5-Benzyloxy-pentyloxy)-phenyl]-2-methoxypropionic
acid 493
[1981] The title compound was prepared from
(2S)-3-[4-(3-hydroxy-phenyl]-2- -methoxy-propionic acid linked to
Wang's Resin (Example 94, Step C) via the Mitsunobu
reaction-cleavage (Standard Procedure G) with
5-benzyloxy-pentan-1-ol. .sup.1H-NMR (200.15 MHz, CDCl.sub.3):
7.4-7.3 (m, 5H), 7.14 (d, 2H, J=8.6), 6.81 (d, 2H, J=8.6), 4.51 (s,
2H), 4.0-3.9 (m, 3H), 3.50 (t, 2H, J=6.2), 3.39 (s, 3H), 3.08 (dd,
1H, J=14.2, 4.3), 2.95 (dd, 1H, J=14.2, 7.5), 1.9-1.5 (m, 6H).
EXAMPLE 251
[1982]
(2S)-2-ethoxy-{4-[3-(4-phenoxy-phenoxy)-propoxy]-phenyl}-propionic
acid 494
[1983] Step A
[1984] (2S)-2-Hydroxy-3-(4-hydroxy-phenyl)-propionic acid ethyl
ester
[1985] A solution of (2S)-2-hydroxy-3-(4-hydroxy-phenyl)-propionic
acid in ethanol and H.sub.2SO.sub.4 (catalytic) was stirred
overnight. The mixture was concentrated to dryness and
reconstituted in ethyl acetate. The organic layer was washed with
NaHCO.sub.3, dried over MgSO.sub.4 and concentrated to dryness to
give the title product. .sup.1H-NMR (CDCl.sub.3, 200.15 MHz):
.delta. 7.03 (d, 2H, J=8.6), 7.00 (d, 2H, J=8.7), 6.72-6.77 (m,
1H), 4.44-4.30 (m, 1H), 4.22 (q, 2H, J=7.9), 3.13-2-77 (m, 2H),
1.24 (t, 3H, J=7.9).
[1986] Step B
[1987]
(2S)-2-Hydroxy-3-{4-[3-(4-phenoxy-phenoxy)-propoxy]-phenyl}-propion-
ic acid ethyl ester
[1988] To a solution of compound (Step A) in DMF, CsCO.sub.3 (1.0
eq) and 4-(3-bromopropoxy)-1-phenoxybenzene (1.1 eq) (Example 244,
Step A) were added. The mixture was stirred at room temperature
overnight. The solvent was concentrated in vacuum and ethyl acetate
was added. The organic layer was washed with water and concentrated
to affrod, after chromatography on silica gel, the title compound.
.sup.1H-NMR (CDCl.sub.3, 200.15 MHz): .delta. 7.28 (dd, 2H, J=8.3,
0.8), 7.17-6.84 (m, 11H), 4.44-4.36 (m, 1H), 4.28-4.12 (m, 6H),
3.13-2.87 (m, 2H), 2.79-2.76 (m, 1H), 2.32-2.19 (m, 2H), 1.29 (t,
3H, J=7.9).
[1989] Step C
[1990]
2-Ethoxy-3-{4-[3-(4-phenoxy-phenoxy)-propoxy]-phenyl}-propionic
acid ethyl ester
[1991] A solution of
(2S)-2-hydroxy-3-{4-[3-(4-phenoxy-phenoxy)-propoxy]-p-
henyl}-propionic acid ethyl ester, AgO.sub.2 (1.5 eq) and ethyl
iodide (excess) in dichloromethane was stirred over 10 days. The
crude mixture was filtered through celite and concentrated to
dryness. The compound was purified by chromatography to give the
title product. .sup.1H-NMR (CDCl.sub.3, 200.15 MHz): .delta.
7.34-7.26 (m, 2H), 7.18-6.82 (m, 11H), 4.18-4.17 (m, 6H), 4.01-3.94
(m, 1H), 3.68-3.53 (m, 1H), 3.43-3.28 (m, 1H), 2.96 (d, 2H, J=6.5),
2.25 (qn, 2H, J=6.2), 1.20 (dt, 6H, J=12.6, 7.3).
[1992] Step D
[1993]
(2S)-2-ethoxy-{4-[3-(4-phenoxy-phenoxy)-propoxy]-phenyl}-propionic
acid
[1994] The title compound was prepared from
2-ethoxy-3-{4-[3-(4-phenoxy-ph- enoxy)-propoxy]-phenyl}-propionic
acid ethyl ester (Step C) by standard hydrolysis procedure C
(LiOH). MS (ES) for C.sub.26H.sub.28O.sub.6 [M+NH.sub.4].sup.+:
454.2, [M-H].sup.-:435.2.
EXAMPLE 252
[1995]
(2S)-2-Benzyloxy-3-{4-[3-phenoxy-phenoxy)-propoxy]-phenyl}-propioni-
c acid 495
[1996] The title compound was prepared as in Example 251 using
benzyl bromide as alkylating agent. Hydrolysis under the Standard
Procedure C of the corresponding ethyl ester derivative gave us the
title compound. MS(ES) for C.sub.3H.sub.30O.sub.6
[M+NH.sub.4].sup.+: 516.2, [M-H].sup.-: 497.2.
EXAMPLE 253
[1997]
(2S)-3-{4-[3-(4-{4-[2-(tert-Butyl-dimethyl-silanyloxy)-ethoxy]-benz-
oyl}-phenoxy)-propoxy]-phenyl}-2-methoxy-propionic acid 496
[1998] Step A
[1999]
(2S)-3-(4-{3-[4-(4-hydroxy-benzoyl)-phenoxy]-propoxy}-phenyl)-2-met-
hoxy-propionic acid ethyl ester 497
[2000] Concentrated sulfuric acid (0.05 mL) was added to a solution
of
(2S)-3-(4-{3-[4-(4-hydroxy-benzoyl)-phenoxy]-propoxy}-phenyl)-2-methoxy-p-
ropionic acid (0.18 mmol, 80 mg) (example 170) in ethanol (20 mL)
at room temperature. The mixture was stirred at room temperature
for three days, and the solvent was concentrated under vacuum.
After addition of water, the mixture was neutralized with solid
NaHCO.sub.3 and extracted with ethyl acetate (3.times.15 mL). The
combined organic layers were dried over MgSO.sub.4, filtered and
concentrated under vacuum to afford the title compound. .sup.1H-NMR
(200.15 MHz, CDCl.sub.3): .delta. 7.76 (d, 2H, J=8.6), 7.71 (d, 2H,
J=8.8), 7.13 (d, 2H, J=8.6), 6.91-6.80 (m, 6H), 6.37 (br s, 1H),
4.25-4.10 (m, 6H), 3.93 (dd, 1H, J=7.0, 5.6), 3.35 (s, 3H), 2.95
(m, 2H), 2.27 (qn, 2H, J=5.9), 1.23 (t, 3H, J=7.1).
[2001] Step B
[2002]
(2S)-3-{4-[3-(4-{4-[2-(tert-Butyl-dimethyl-silanyloxy)-ethoxy]-benz-
oyl}-phenoxy)-propoxy]-phenyl}-2-methoxy-propionic acid ethyl ester
498
[2003] Diisopropyl azodicarboxilate (0.2 mmol, 0.04 mL) was added
dropwise to a solution of
2-(tert-butyl-dimethyl-silanyloxy)-ethanol (0.26 mmol, 46 mg)
(Example 122, Step A), (2S)-3-(4-{3-[4-(4-hydroxy-benzoyl)-phenoxy-
]-propoxy}-phenyl)-2-methoxy-propionic acid ethyl ester (0.13 mmol,
65 mg) and triphenylphosphine (0.2 mmol, 38 mg) in anhydrous
toluene (2 mL) at 0.degree. C. under nitrogen. The mixture was
stirred overnight at room temperature, quenched with water and
extracted with ethyl acetate (3.times.15 mL). The combined organic
layers were dried over MgSO.sub.4, filtered and concentrated under
vacuum. The crude mixture was chromatographed on silica gel using a
4/1 hexane/EtOAc mixture as eluent to afford the title product
.sup.1H-NMR (200.15 MHz, CDCl.sub.3): .delta. 7.76 (d, 4H, J=8.9),
7.13 (d, 2H, J=8.6), 6.96 (d, 4H, J=8.6), 6.83 (d, 2H, J=8.6),
4.26-4.09 (m, 8H), 4.02-3.87 (m, 3H), 3.35 (s, 3H), 2.97 (m, 2H),
2.28 (qn, 2H, J=5.9), 1.23 (t, 3H, J=7.1), 0.91 (s, 9H), 0.11 (s,
6H).
[2004] Step C
[2005] (2S)-3-{4-[3-(4-{4-[2-(tert-Butyl
dimethyl-silanyloxy)-ethoxy]-benz-
oyl}-phenoxy)-propoxy]-phenyl}-2-methoxy-propionic acid
[2006] The title compound was prepared from
(2S)-3-{4-[3-(4-{4-[2-tert-But-
yl-dimethyl-silanyloxy)-ethoxy]-benzoyl}-phenoxy)-propoxy]-phenyl}-2-metho-
xy-propionic acid ethyl ester by the standard hydrolysis procedure
C (LiOH). .sup.1H-NMR (200.15 MHz, CDCl.sub.3): .delta. 7.76 (dd,
4H, J=8.6, 1.6), 7.15 (d, 2H, J=8.6), 6.95 (dd, 4H, J=8.8, 1.6),
6.83 (d, 2H, 8-0.6), 4.24 (t, 2H, J=6.0), 4.17-4.09 (m, 5H),
4.02-3.94 (m, 3H), 3.39 (s, 3H), 3.12-2.90 (m, 2H), 2.27 (qn, 2H,
J=6.0), 0.91 (s, 9H), 0.11 (s, 6H).
EXAMPLE 254
[2007]
(2S)-3-[4-(3-{4-[4-(2-Hydroxy-ethoxy)-benzoyl]-phenoxy}-propoxy)-ph-
enyl]-2-methoxy-propionic acid 499
[2008] The compound of
2S)-3-{4-[3-(4-{4-[2-(tert-butyl-dimethyl-silanylox-
y)-ethoxy]-benzoyl}-phenoxy)-propoxy]-phenyl}-2-methoxy-propionic
acid (Example 253, Step C) (0.05 mmol, 30 mg) was dissolved in 5 mL
of a mixture of acetic acid, THF and H.sub.2O (3:1:1) and stirred
at room temperature for 2 hours. The mixture was diluted with
H.sub.2O and extracted with ethyl acetate (4.times.20 mL). The
combined organic layers were dried over MgSO.sub.4, filtered and
concentrated under vacuum to afford the title compound. MS(ES) for
C.sub.28H.sub.30O.sub.8 [M+H].sup.+: 495.1
EXAMPLE 255
[2009]
(2S)-3-{4-[3-(4-phenoxy-phenoxy)-propoxy]-phenyl}2-propoxy-propioni-
c acid 500
[2010] Step A
[2011] 3-(4-Benzyloxy-phenyl-2-hydroxy-propionic acid ethyl ester
501
[2012] A mixture of 2-hydroxy-3-(4-hydroxy-phenyl)-propionic acid
ethyl ester (Example 251, Step A) (5.2 mmol, 1.1 g), benzyl bromide
(5.2 mmol, 0.62 mL) and potassium carbonate (15.7 mmol, 2.2 g) in
acetonitrile (20 mL) was refluxed overnight. The mixture was cooled
down to room temperature and concentrated to dryness to give a
crude, which was purified by column chromatography on, silica gel
to afford the title product.
[2013] MS (ES) for C.sub.18H.sub.20O.sub.4 [M+NH.sub.4].sup.+:
318.3
[2014] Step B
[2015] (2S)-2-Allyloxy-3-(4-benzyloxy-phenyl)-propionic acid ethyl
ester 502
[2016] Silver (1) oxide (5.7 mmol, 1.3 g) was added to a mixture of
(S)-3-(4-benzyloxy-phenyl)-2-hydroxy-propionic acid ethyl ester
(3.8 mmol, 1.2 g) and alkyl bromide (19 mmol, 1.6 mL) in DMF (10
mL) at room temperature, and the reaction mixture was heated at
50.degree. C. for 20 hours. After cooling to room temperature, the
mixture was diluted with H.sub.2O and extracted with ethyl acetate
(5.times.25 mL). The combined organic layers were washed with water
(4.times.20 mL) and brine; dried over MgSO.sub.4, filtered and
concentrated under vacuum. The crude mixture was chromatographed on
silica gel using a 4/1 hexane/ethyl acetate mixture as eluent to
afford the title product. .sup.1H-NMR (200.15 MHz, CDCl.sub.3):
.delta. 7.46-7.32 (m, 5H), 7.18 (d, 2H, J=8.9), 6.91 (d, 2H,
J=8.9), 5.91-5.72 (m, 1H), 5.25-5.12 (m, 2H), 5.05 (s, 2H),
4.11-4.03 (4H, m), 3.94-3.84 (m, 1H), 2.99 (d, 2H, J=7.0), 1.23 (t,
3H, J=7.0).
[2017] Step C
[2018] (2S)-3-(4-Hydroxy-phenyl)-2-propoxy-propionic acid ethyl
ester 503
[2019] A mixture of (S)-2-allyloxy-3-(4-benzyloxy-phenyl)-propionic
acid ethyl ester (1.33 mmol, 450 mg) and 10% Pd/C (45 mg) in EtOH
(15 mL) were stirred under hydrogen atmosphere (1 atm) for 18
hours. The mixture was filtered through celite and concentrated
under vacuum to afford the title product. .sup.1H-NMR (200.15 MHz,
CDCl.sub.3): .delta. 7.10 (d, 4H, J=8.6), 6.73 (d, 2H, J=8.4), 5.90
(brs, 1H), 4.16 (q, 2H, J=7.3), 3.94 (t, 1H, J=6.7), 3.53-3.45 (m,
1H), 3.27-3.16 (m, 1H), 2.93 (d, 2H, J=6.5), 1.54 (m, 2H), 1.22 (t,
3H, J=7.3), 0.84 (t, 3H, J=7.5).
[2020] Step D
[2021]
(2S)-3-{4-[3-(4-phenoxy-phenoxy)-propoxy]-phenyl}-2-propoxy-propion-
ic acid ethyl ester 504
[2022] The title compound was prepared
from(S)-3-hydroxy-phenyl)-2-propoxy- -propionic acid ethyl ester
and 3-(4-phenoxy-phenoxy)-propyl bromide (Example 244) using the
Standard Procedure L. The product was purified by column
chromatography on silica gel using 9/1 Hexan/Ethyl acetate mixture
as eluent to afford the title product. MS(ES) for
C.sub.29H.sub.34O.sub.6 [M+NH.sub.4].sup.+: 496.3
[2023] Step E
[2024]
(2S)-3-{4-[3-(4-phenoxy-phenoxy)-propoxy]-phenyl}-2-propoxy-propion-
ic acid
[2025] The title compound was prepared from
(S)-3-{4-[3-(4-phenoxy-phenoxy-
)-propoxy]-phenyl}-2-propoxy-propionic acid ethyl ester by the
standard hydrolysis procedure C (LiOH). MS(ES) for
C.sub.27H.sub.30O.sub.6 [M-H].sup.-: 449.2
EXAMPLE 256
[2026] (2S)-3-{4-[3-(4-Benzoyl
phenoxy)-propoxy]-phenyl}-2-ethoxy-propioni- c acid 505
[2027] Step A
[2028]
(2S)-3-{4-[3-(4-Benzoyl-phenoxy)-propoxy]-phenyl}-2-ethoxy-propioni-
c acid methyl ester 506
[2029] The title compound was prepared from
2-ethoxy-3-(4-hydroxy-phenyl)-- propionic acid methyl ester and
[4-(3-bromo-propoxy)-phenyl]-phenyl-methan- one (prepared from
4-hydroxybenzophenone following the same procedure as in (Example
132, Steps B to D) using the Standard Procedure I. The product was
purified by col chromatography on silica gel using a hexane/ethyl
acetate mixture (4/1) as eluent to give the racemic product. This
racemic mixture was subjected to chiral HPLC separation to give the
pure enantiomer. .sup.1H-NMR (200.15 MHz, CDCl.sub.3): .delta.
7.83-7.72 (m, 4H), 7.57-7.42 (m, 3H), 7.14 (d, 2H, J=8.8), 6.96 (d,
2H, J=8.8), 6.83 (d, 2H, J=8.6), 4.25 (t, 2H, J=6.1), 4.15 (t, 2H,
J=6.2), 3.98 (dd, 1H, J=7.1, 6.0), 3.70 (s, 3H), 3.58 (dd, 1H,
J=9.1, 7.0), 3.33 (dd, 1H, J=9.1, 7.0), 2.94 (m, 2H), 2.28 (qn, 2H,
J=6.2), 1.25 (t, 3H, J=7.3).
[2030] Step B
[2031]
(2S)-3-{4-[3-(4-Benzoyl-phenoxy)-propoxy]-phenyl}-2-ethoxy-propioni-
c acid
[2032] The title compound was prepared from
(S)-3-{4-[3-(4-Benzoyl-phenoxy-
)-propoxy]-phenyl}-2-ethoxy-propionic acid methyl ester by the
standard hydrolysis procedure C (LiOH). MS(ES) for
C.sub.27H.sub.28O.sub.6 [M-H].sup.-: 447.1
EXAMPLE 257
[2033]
(2S)-3-{4-[3-(4-Benzyl-phenoxy)-propoxy]-phenyl}-2-ethoxy-propionic
acid 507
[2034] Step A
[2035]
(2S)-3-{4-[3-(4-Benzyl-phenoxy)-propoxy]-phenyl}-2-ethoxy-propionic
acid ethyl ester 508
[2036] The title compound was prepared from
(S)-2-ethoxy-3-(4-hydroxy-phen- yl)-propionic acid ethyl ester and
3-(4-benzyl-phenoxy)-propyl bromide (prepared from 4-benzylphenol
following the same procedure as in (Example 132, Steps B to D)
using the Standard Procedure I. The product was purified by column
chromatography on silica gel using a hex ae/ethyl acetate mixture
(4/1) as eluent to give the title product. MS(ES) for
C.sub.9H.sub.34O.sub.5 [M+NH.sub.4].sup.+: 480.2
[2037] Step B
[2038]
(2S)-3-{4-[3-(4-Benzyl-phenoxy)-propoxy]-phenyl}-2-ethoxy-propionic
acid
[2039] The title compound was prepared from
(S)-3-{4-[3-(4-Benzyl-phenoxy)-
-propoxy]-phenyl}-2-ethoxy-propionic acid ethyl ester by the
standard hydrolysis procedure C (LiOH). MS(ES) for
C.sub.27H.sub.30O.sub.5 [M-H].sup.-: 433.1
EXAMPLE 258
[2040]
(2S)-3-{4-[3-(4-Benzoyl-phenoxy)-propoxy]-3-chloro-phenyl}-2-ethoxy-
-propionic acid 509
[2041] Step A
[2042] (2S)-3-(3-Chloro-4-hydroxy-phenyl)-2-ethoxy-propionic acid
ethyl ester 510
[2043] N-Chlorosuccinimide (2.1 mmol) was added to a solution of
(S)-2-ethoxy-3-(4-hydroxy-phenyl)-propionic acid ethyl ester (2.1
mmol) in acetonitrile (12 mL) at room temperature, and the mixture
was stirred at the same temperature for 5 days. Solvent was
evaporated under vacuum, and the residue was washed with CCl.sub.4.
The resulting suspension was filtered, and the filtrate was
concentrated under vacuum and chromatographed on silica gel using a
9/1 hexane/EtOAc mixture as eluent to afford title product. MS(ES)
for C.sub.13H.sub.17ClO.sub.4 [M-H].sup.-: 271.0
[2044] Step B
[2045]
(2S)-3-{4-[3-(4-benzoyl-phenoxy)-propoxy]-3-chloro-phenyl}-2-ethoxy-
-propionic acid ethyl ester 511
[2046] The title compound was prepared from
(S)-2-ethoxy-3-(3-chloro-4-hyd- roxy-phenyl)-propionic acid ethyl
ester and [4-(3-bromo-propoxy)-phenyl]-p- henyl-methanone (Example
256) using the Standard Procedure I. The product was purified by
column chromatography on silica gel using a 4/1 Hexane/Ethyl
acetate mixture as eluent to give the title product. MS(ES) for
C.sub.29H.sub.31ClO.sub.6 [M+H].sup.+: 511.1
[2047] Step C
[2048]
(2S)-3-{4-[3-(4-benzoyl-phenoxy)-propoxy-3-chloro-phenyl}-2-ethoxy--
propionic acid
[2049] The title compound was prepared from
(S)-3-{4-[3-(4-benzoyl-phenoxy-
)-propoxy]-3-chloro-phenyl}-2-ethoxy-propionic acid methyl ester by
the standard hydrolysis procedure C (LiOH). .sup.1H-NMR (200.15
MHz, CDCl.sub.3): .delta. 7.82-7.72 (m, 4H), 7.56-7.43 (m, 3H),
7.07 (dd, 1H, J=8.8, 2.0), 6.97 (d, 2H, J=8.9), 6.86 (d, 2H,
J=8.3), 4.31 (t, 2H, J=6.0), 4.21 (t, 2H, J=6.0), 4.10-4.02 (m,
1H), 3.66-3.44 (m, 2H), 3.10-2.87 (m, 2H), 2.33 (qn, 2H, J=6.2),
1.20 (t, 3H, J=7.0).
EXAMPLE 259
[2050]
(2S)-4'-{3-[4-(2-Carboxy-2-methoxy-ethyl)-2-methoxy-phenoxy]-propox-
y}-biphenyl-4-carboxylic acid 512
[2051] Step A
[2052]
3-[4-(3-Hydroxy-propoxy)-3-methoxy-phenyl]-2-methoxypropionic acid
methyl ester 513
[2053] A mixture of
3-(4-Hydroxy-3-methoxy-phenyl)-2-methoxypropionic acid methyl ester
(Example 130, Step B) and 3-(tert-butyl
dimethyl-silanyloxy)-propan-1-ol were treated under Mitsunobu
standard conditions B using DIAD and toluene. The product obtained
was treated under Standard Procedure E for cleavage protected
alcohols to give the title product. The (2S) isomer was separated
from the 2R isomer by chiral. .sup.1H-NMR (CDCl.sub.3, 200.15 MHz):
.delta. 6.94-6.72 (m, 3H), 4.17 (t, 2H, J=5.9), 3.94 (dd, 2H,
J=7.0, 5.4), 3.87 (t, 2H, J=5.4), 3.84 (s, 3H), 3.73 (s, 3H), 3.35
(s, 3H), 2.97-2.93 (m, 2H), 2.11-2.00 (m, 2H).
[2054] Step B
[2055]
(2S)-4'-{3-[2-Methoxy-4-(2-methoxy-2-methoxycarbonyl-ethyl)-phenoxy-
]-propoxy}-biphenyl-4-carboxylic acid methyl ester 514
[2056] 3-[4-(3-Bromo-propoxy)-3-methoxy-phenyl]-2-methoxy-propionic
acid methyl ester (Step A) and 4'-hydroxy-biphenyl-4-carboxylic
acid methyl ester (Example 197, Step A) were treated under
Mitsunobu standard condition B. The crude was purified by
chromatography on silica gel (hexanes/ethyl acetate 7:3) to afford
the title compound.
[2057] .sup.1H-NMR (CDCl.sub.3, 200.15 MHz): .delta. 8.07 (d, 2H,
J=8.6), 7.58 (dd, 4H, J=10.8, 8.9), 7.14 (d, 2H, J=8.9), 6.99 (d,
2H, J=8.9), 6.84 (d, 2H, J=8.6), 4.24-4.12 (m, 6H), 3.94-3.90 (m,
4H), 3.35 (s, 3H), 2.97-2.94 (m, 2H), 2.27 (qn, 2H, J=5.9), 1.23
(t, 3H, J=7.0).
[2058] Step C
[2059]
(2S)-4'-{3-[4-(2-Carboxy-2-methoxy-ethyl)-2-methoxy-phenoxy]-propox-
y}-biphenyl-4-carboxylic acid
[2060] The title compound was prepared from
4'-{3-[2-methoxy-4-(2-methoxy--
2-methoxycarbonyl-ethyl)-phenoxy]-propoxy}-biphenyl-4-carboxylic
acid methyl ester (Step B) by standard hydrolysis procedure C
(NaOH). .sup.1H-NMR (MeOD, 300.15 MHz): .delta. 8.07 (d, 2H,
J=8.5), 7.69 (d, 2H, J=8.5), 7.63 (d, 2H, J=8.7), 7.06 (d, 2H,
J=8.7), 6.91-6.88 (m, 2H), 6.78 (dd, 1H, J=8.1, 1.6), 4.25 (t, 2H,
J=6.3), 4.18 (t, 2H, J=6.0), 3.94 (dd, 1H, J=7.9, 4.4), 3.82 (s,
3H), 3.33 (s, 3H), 3.01 (dd, 1H, J=14.1, 4.4), 2.88 (dd, 1H,
J=13.9, 7.7), 2.26 (qn, 2H, J=6.0).
EXAMPLE 260
[2061]
(2S)-3-{4-[3-(4'-tert-Butyl-biphenyl-4-yloxy)-propoxy]-2-methoxy-pr-
opionic acid 515
[2062] Step A
[2063] 3-Bromopropan-1-ol 516
[2064] To a solution of 1,3-propanediol (5 g, 66 mmol) and benzene
(132 mL) was added hydrobromic acid 48% (8 mL). The resulting
mixture was heated at reflux for 20 hours while trapping the water
formed using a Dean-Stark water separator. The mixture was washed
with 2N NaOH solution, 5% HCl, water and brine. The organic layer
was dried (Na.sub.2SO.sub.4) and evaporated under reduced pressure.
.sup.1H-NMR (CDCl.sub.3, 300.15 MHz): .delta. 3.78 (2H, t, J=6.0),
3.52 (2H, t, J=6.0), 2.07 (2H, m).
[2065] Step B
[2066] 3-[4-(3-Bromo-propoxy)-2-methoxy-phenyl]-2-methoxy-propionic
acid methyl ester 517
[2067] 3-(4-Hydroxy-2-methoxy-phenyl)-2-methoxy-propionic acid
methyl ester (Example 188, Step C) and 3-bromo-propan-1-ol (Step A)
were treated in the standard Mitsunobu conditions B (DIAD/toluene)
to afford the title compound. .sup.1H-NMR (CDCl.sub.3, 200.15 MHz):
.delta. 7.01 (d, 1H, J=8.3), 6.39 (m, 2H), 4.06 (t, 2H, J=5.9),
4.00-3.96 (m, 1H), 3.78 (s, 3H), 3.67 (s, 3H), 3.57 (t, 2H, J=6.4),
3.31 (s, 3H), 2.99 (dd, 1H, J=13.7, 6.2), 2.91 (dd, 1H, J=13.7,
7.5), 2.34-2.22 (m, 2H).
[2068] Step C
[2069]
(2S)-3-{4-[3-(4'-tert-Butyl-biphenyl-4-yloxy)-propoxy-2-methoxy-phe-
nyl]-2-methoxy-propionic acid methyl ester 518
[2070]
3-[4-(3-]3-Bromo-propoxy)-2-methoxy-phenyl]-2-methoxy-propionic
acid methyl ester (Step B) and 4'-tert-butyl-biphenyl-4-ol (Example
221, Step A) were treated under Standard Procedure K. The
enantiomers were separated by chiral HPLC. The (2S) isomer was
separated from the 2R isomer by chiral HPLC (Chiralpack AD, Hexane
0.05% TFA/IPA, 75/25, isocratic mode, 1 mL/min; RT=7.70 min).
.sup.1H-NMR (CDCl.sub.3, 200.15 MHz): .delta. 7.53-7.41 (m, 6H),
7.05-6.95 (m, 3H), 6.45-6.40 (m, 2H), 4.21 (d, 2H, J=6.2), 4.14 (d,
2H, J=6.2), 4.05-3.98 (m, 1H), 3.80 (s, 3H), 3.69 (s, 3H), 3.33 (s,
3H), 3.01 (dd, 1H, J=13.4, 6.2), 2.92 (dd, 1H, J=13.4, 7.5), 2.27
(qn, 2H, J=6.2).
[2071]
(2S)-3-{4-[3-(4'-tert-Butyl-biphenyl-4-yloxy)-propoxy]-2-methoxy-ph-
enyl}-2-methoxy-propionic acid
[2072] The title compound was prepared from
(2S)-3-{4-[3-(4'-tert-butyl-bi-
phenyl-4-yloxy)-propoxy]2-methoxy-phenyl}-2-2-methoxy-propionic
acid methyl ester (Step C) by standard hydrolysis procedure C
(NaOH). .sup.1H-NMR (Acetone-d.sub.4, 300.15 MHz): .delta. 7.57 (d,
2H, J=8.7), 7.53 (d, 2H, J=8.7), 7.45 (d, 2H, J=8.5), 7.06-7.02 (m,
3H), 6.55 (d, 1H, J=2.0), 6.46 (dd, 1H, J=8.3, 2.2), 4.26-4.17 (m,
4H), 3.96 (dd, 1H, J=7.9, 5.7), 3.81 (3H), 3.26 (s, 3H), 2.25 (qn,
2H, J=0.3), 1.33 (s, 9H).
EXAMPLE 261
[2073]
(2S)-3-(4-{3-[Hydroxy-phenoxy)-phenoxy]-propoxy}-phenyl)-2-methoxy--
propionic acid 519
[2074]
(2)-3-{4-[3-(tert-Butyl-dimethyl-silanyloxy)-propoxy]-phenyl}-2-met-
hoxy-propionic acid ethyl ester 520
[2075] A mixture of (2S)-3-(4-hydroxy-phenyl)-2-methoxy propionic
acid ethyl ester and 3-(tert-Butyl-dimethyl-silanyloxy)-propan-1-ol
were treated under Mitsounobu coupling standard conditions B using
DIAD and toluene.
[2076] Step B
[2077] (2S)-3-[4-(3-Hydroxy-propoxy)-phenyl]-2-methoxy-propionic
acid ethyl ester 521
[2078] A solution of
(2S)-3-{4-[3-(tert-Butyl-dimethyl-silanyloxy)-propoxy-
]-phenyl}-2-methoxy-propionic acid ethyl ester was treated under
Standard Procedure E for cleaveage protected alcohols to give the
title product.
[2079] Step C
[2080]
3-(4-{3-[4'-(tert-Butyl-dimethyl-silanyloxy)-biphenyl-4-yloxy]-prop-
oxy}-phenyl)-2-methoxy-propionic acid ethyl ester 522
[2081] (2S)-3-[4-(3-Hydroxy-propoxy)-phenyl)-2-methoxy-propionic
acid ethyl ester and
4'-(tert-butyl-dimethyl-silanyloxy)-biphenyl-4-ol (Example 196,
Step A) were treated under Mitsunobu procedure B (DIAD, toluene),
to afford the title compound.
[2082] Step D
[2083]
(2S)-3-(4-{3-[4-(4-Hydroxy-propoxy)-phenoxy]-propoxy}-phenyl)-2-met-
hoxy-propionic acid
[2084] The title compound was prepared from
3-(4-{3-[4'-(tert-butyl-dimeth-
yl-silanyloxy)-biphenyl-4-yloxy]-propoxy}-phenyl)-2-methoxy-propionic
acid ethyl ester (Step A) by standard hydrolysis procedure C
(NaOH). .sup.1H-NMR (CDCl.sub.3, 200.15 MHz): .delta. 7.15 (d, 2H,
J=8.6), 6.92-6.74 (m, 10H), 4.15-4.09 (m, 4H), 3.98 (dd, 1H, J=7.3,
4.6), 3.39 (s, 3H), 3.09 (dd, 1H, J=14.2, 4.6), 2.95 (dd, 1H,
J=14.2, 7.3), 2.23 (qn, 2H, J=5.9).
EXAMPLE 262
[2085]
(2S)-2-Methoxy-3-(4-{3-[4-(2,2,3,3-tetrafluoro-propoxy)-phenoxy]-pr-
opoxy}-phenyl)-propionic acid 523
[2086] Step A
[2087] 4-(2,2,3,3-tetrafluoro-propoxy)-1-benzyloxy-phenol 524
[2088] To a solution of methanesulfonic acid
2,2,3,3-tetrafluoropropyl ester (obtained from
2,2,3,3-tetrafluoropropanol and methanesulfonyl chloride as
described in (Example 268, Step A) (0.35 mmol, 74 mg) and
4-benzyloxy-phenol (0.175 mmol, 35 mg) in DMF (1 mL) was added
K.sub.2CO.sub.3, and the was stirred at 100.degree. C. for 20
hours. Waiter: was added and the aqueous layer was extracted twice
with hexane and once with ethyl acetate. The combined organic
layers were dried (Na.sub.2SO.sub.4), filtered and evaporated. The
crude was purified by chromatography on silica gel (hexane/ethyl
acetate 4:1) to afford the title compound. .sup.1H-NMR (CDCl.sub.3,
200.15 MHz): .delta. 7.42-7.32 (m, 5H, 6.96-6.84 (m, 4H), 6.06 (t,
1H, J=53.0, 5.1), 5.03 (s, 2H), 4.29 (dt, J=12.0, 1.6).
[2089] Step B
[2090] 4-(2,2,3,3-Tetrafluoro-propoxy)-phenol 525
[2091] 4-(2,2,3,3-tetrafluoro-propoxy)-benzyloxy-phenol (0.09 mmol,
28 mg) (Step A) was dissolved in MeOH (2 mL) and Pd(C) (40% weight,
10 mg) was added. The mixture was stirred for 90 minutes under
H.sub.2 atmosphere (1 atm), and filtered through a celite pad
(EtOH). The filtrate was concentrated to give the title compound.
.sup.1H-NMR (CDCl.sub.3, 200.15 MHz): 56.85-6.75 (m, 4H), 6.05 (dt,
J=53.2, 4.8), 4.28 (dt, 2H, J=12.1, 1.6).
[2092] Step C
[2093]
(2S)-2-Methoxy-3-(4-{3-[4-(2,2,3,3-tetrafluoro-propoxy)-phenoxy]-pr-
opoxy}-phenyl)-propionic acid ethyl ester 526
[2094] 3-[4-(3-Bromo-propoxy)-phenyl]-2-methoxy-propionic acid
ethyl ester (Example 173, Step A) and
4-(2,2,3,3-tetrafluoro-propoxy)-phenol (Step B) were treated under
ester K to afford the title compound .sup.1H-NMR (CDCl.sub.3,
200.15 MHz): .delta. 7.13 (d, 2H, J=8.6), 6.85-6.80 (m, 6H), 6.05
(dt, 1H, J=53.2, 5.1), 4.22-4.08 (m, 8H), 3.90 (dd, 1H, J=7.0,
5.6), 3.35 (s, 3H), 3.04-2.86 (m, 2H), 2.22 (qn, 2H, J=6.2).
[2095] Step D
[2096]
(2S)-2-Methoxy-3-(4-{3-[4-(2,2,3,3-tetrafluoro-propoxy)-phenoxy]-pr-
opoxy}-phenyl)-propionic acid
[2097] The title compound was prepared from
(2S)-2-methoxy-3-(4-{3-[4-(2,2-
,3,3-tetrafluoro-propoxy)-phenoxy]-propoxy}-phenyl)-propionic acid
ethyl ester (Step C) by standard hydrolysis procedure C (NaOH).
.sup.1H-NMR (CDCl.sub.3, 200.15 MHz): .delta. 7.14 (d, 2H, J=8.6),
6.84-6.79 (m, 6H), 6.04 (tt, 1H, J=53.0, 4.8), 4.27 (t, 2H,
J=12.0), 4.09 (t, 4H, J=5.9), 3.97-3.91 (m, 1H), 3.34 (s, 3H),
3.11-2.87 (m, 2H), 2.20 (qn, 2H, J=5.9).
EXAMPLE 263
[2098]
(2S)-2-Methoxy-3-(4-{3-[4-(3-methyl-butoxy)-phenoxy]-propoxy}-pheny-
l)-propionic acid 527
[2099] Step A
[2100] 2S)-3-{4-[3-(4-benzyloxy-phenoxy]-phenoxy}-phenyl)-2-methoxy
propionic acid ethyl ester 528
[2101] 3-[4-(3-Bromo-propoxy)-3-methoxy-phenyl]-2-methoxy-propionic
acid methyl ester (Example 175, Step B) and 4-benzyloxy-phenol were
treated under Mitsunobu standard conditions B to afford the title
compound. .sup.1H-NMR (CDCl.sub.3, 200.15 MHz): .delta. 7.44-7.30
(m, 5H), 7.13 (d, 2H, J=8.6), 6.93-6.73 (m, 6H), 5.01 (s, 2H),
4.20-4.06 (m, 6H), 3.90 (dd, 1H, J=7.0, 5.6), 3.35 (s, 3H),
3.00-2.93 (m, 2H), 2.22 (qn, 2H, J=6.2), 1.23 (t, 3H, J=7.2).
[2102] Step B
[2103]
(2S)-3-{4-[3-(4-Hydroxy-phenoxy)-propoxy]-phenyl}-2-methoxy-propion-
ic acid ethyl ester 529
[2104] The title compound was obtained following the hydrogenation
procedure (Example 261, Step B), starting from
(2S)-3-{4-[3-(4-benzyloxy-- phenoxy]-propoxy}-phenyl) 2-methoxy
propionic acid ethyl ester. .sup.1H-NMR (CDCl.sub.3, 200.15 MHz):
.delta. 7.13 (d, 2H, J=8.9), 6.84-6.71 (m, 6H), 4.23-4.06 (m, 6H),
3.91 (dd, 1H, J=7.3, 5.9), 3.35 (s, 3H), 2.97-2.93 (m, 2H), 2.21
(qn, 2H, J=6.2), 1.23 (t, 3H, J=7.3).
[2105] Step C
[2106]
(2S)-2-Methoxy-3-(4-{3-[3-methyl-butoxy)-phenoxy]-propoxy}-phenyl)--
propionic acid ethyl ester 530
[2107]
(2S)-3-{4-[3-(4-Hydroxy-phenoxy)-propoxy]-phenyl}-2-methoxy-propion-
ic acid ethyl ester (Step A) was reacted under Mitsunobu procedure
B (DIAD, toluene) with 3-methyl-butanol to afford the title
compound. .sup.1H-NMR (CDCl.sub.3, 200.15 MHz): .delta. 7.13 (d,
2H, J=8.6), 6.85-6.81 (m, 6H), 4.18 (q, 4H, J=7.0), 4.08 (d, 2H,
J=5.9), 3.96-3.87 (m, 3H), 3.35 (s, 3H), 2.97-2.93 (m, 2H), 2.22
(qn, 2H, J=6.2), 1.86-1.60 (m, 3H), 1.23 (t, 5H, J=7.0), 0.95 (d,
6H, J=6.4).
[2108] Step D
[2109]
(2S)-2-Methoxy-3-(4-{3-[3-methyl-butoxy)-phenoxy]-propoxy}-phenyl)--
propionic acid
[2110] The title compound was prepared from
(2S)-2-methoxy-3-(4-{3-[4-(3-m-
ethyl-butoxy)-phenoxy]-propoxy}-phenyl)-propionic acid ethyl ester
(Step B) by standard hydrolysis procedure C (NaOH). .sup.1H-NMR
(CDCl.sub.3, 200.15 MHz): .delta. 7.12 (d, 2H, J=8.4), 6.84-6.80
(m, 6H), 4.09 (q, 4H, J=6.2), 3.99-3.88 (m, 3H), 3.37 (s, 3H), 3.07
(dd, 1H, J=14.3, 4.4), 2.93 (dd, 1H, J=14.3, 7.0), 2.19 (qn, 2H,
J=6.2), 1.90-1.71 (m, 1H), 1.62 (q, 2H, J=6.9), 0.93 (d, 1H,
J=6.6).
EXAMPLE 264
[2111]
(2S)-3-{4-[3-(4-Hydroxy-phenoxy)-propoxy]-phenyl}-2-methoxy-propion-
ic acid 531
[2112]
(2S)-3-{4-[3-(4-Hydroxy-phenoxy)-propoxy]-phenyl}-2-methoxy-propion-
ic acid ethyl ester (Example 263, Step B) was coupled under the
ester J with 1-bromo-2-methylpropane to afford the title compound.
.sup.1H-NMR (CDCl.sub.3, 200.15 MHz): .delta. 7.14 (d, 2H, J=8.6),
6.86-6.82 (m, 6H), 4.11 (q, 4H, J=6.2), 3.98 (dd, 1H, J=7.3, 4.6),
3.66 (d, 2H, J=6.5), 3.40 (s, 3H), 3.10 (dd, 1H, J=14.5, 4.6), 2.95
(dd, 1H, J=14.5, 7.3), 2.21 (qn, 2H, J=6.2), 2.11-1.98 (m, 1H),
1.01 (d, 6H, J=6.7).
EXAMPLE 265
[2113]
(2S)-3-{4-[3-(4-Isopropoxy-phenoxy]-propoxy}-phenyl-2-methoxy-propi-
onic acid 532
[2114] The title compound was prepared from
(2S)-3-{4-[3-(4-hydroxy-phenox-
y)-propoxy]-phenyl}-2-methoxy-propionic acid ethyl ester (Example
263, Step B) and 2-bromopropene following the procedure described
for Example 264. .sup.1H-NMR (CDCl.sub.3, 200.15 MHz): .delta. 7.14
(d, 2H, J=8.3), 6.86-6.82 (m, 6H), 4.40 (qn, 1H, J=5.9), 4.11 (q,
4H, J=5.9), 3.98 (dd, 1H, J=7.3, 4.6), 3.40 (s, 3H), 30.0 (dd, 1H,
J=14.2, 4.3), 3.01-2.90 (dd, 1H, J=14.2, 7.2), 2.22 (qn, 2H,
J=5.9), 1.30 (d, 6H, J=6.2).
EXAMPLE 266
[2115]
(2S)-3-{4-[3-(4-Cyclohexylmethoxy-phenoxy)-propoxy]-phenyl}-2-metho-
xy-propionic acid 533
[2116] The title compound was prepared from
(2S)-3-{4-[3-(4-hydroxy-phenox-
y)-propoxy]-phenyl}-2-methoxy-propionic acid ethyl ester (Example
263, Step B) and (bromomethyl)cyclohexane following the procedure
described for Example 264.
[2117] .sup.1H-NMR (CDCl.sub.3, 200.15 MHz): .delta. 7.14 (d, 2H,
J=8.6), 6.86-6.81 (m, 6H), 4.11 (q, 4H, J=6.2), 3.99 (dd, 1H,
J=7.3, 4.6), 3.70 (d, 2H, J=6.2), 3.40 (s, 3H), 3.10 (dd, 1H,
J=14.5, 4.6), 2.96 (dd, 1H, J=14.2, 7.3), 2.23 (qn, 2H, J#6.2),
1.88-1.67 (m, 6H), 1.39-0.94 (m, 5H).
EXAMPLE 267
[2118]
(2S)-2-Methoxy-3-{4-[3-(4-phenetyloxy-phenoxy)-propoxy]-phenyl}-pro-
pionic acid 534
[2119] The title compound was prepared from
(2S)-3-{4-[3-(4-hydroxy-phenox-
y)-propoxy]-phenyl}-2-methoxy-propionic acid ethyl ester (Example
263, Step B) and (1-bromoethyl)benzene following the procedure
described for Example 264. .sup.1H-NMR (CDCl.sub.3; 300.15 MHz):
.delta. 7.32-7.26 (m, 5H), 7.14 (d, 2H, J=8.5), 6.86-6.82 (m, 6H),
4.15-4.08 (m, 6H), 4.00 (dd, 1H, J=6.9, 4.4), 3.41 (s, 3H),
3.14-3.05 (m, 3H), 2.97 (dd, 1H, J=14.5, 6.9), 2.22 (qn, 2H,
J=6.1).
EXAMPLE 268
[2120]
(2S)-3-(4-{3-[4-(3-Dimethylamino-propoxy)-phenoxy]-propoxy}-phenyl)-
-2-methoxy-propionic acid 535
[2121] Step A
[2122] Methanesulfonic acid 3-dimethylamino-propyl ester 536
[2123] 3-Dimethylamino-1-propanol (0.98 mmol, 0.12 mL) was
dissolved in THF (2 mL). Triethylamine (1.47 mmol, 0.20 mL) was
added, and the mixture was cooled at 0.degree. C. Methanesulfonyl
chloride (1.08 mmol, 0.08 mL). Was added and the bath removed. The
mixture was warmed to room temperature and stirred for 2 hours.
Hexanes were added and the precipitates were removed by filtration
through celite (hexanes). The filtrate was concentrated to afford
the title compound. .sup.1H-NMR (CDCl.sub.3, 200.15 MHz): .delta.
4.29 (t, 2H, J=6.4), 3.00 (s, 3H), 2.39 (t, 2H, J=7.0), 2.22 (s,
6H), 1.90 (qn, 2H, J=6.7).
[2124] Step B
[2125]
(2S)-3-(4-{3-[4-(3-Dimethylamino-propoxy)-phenoxy]-propoxy}-phenyl)-
-2-methoxy-propionic acid
[2126] The title compound was prepared from
(2S)-3-{4-[3-(4-hydroxy-phenox-
y)-propoxy]-phenyl}-2-methoxy-propionic acid ethyl ester (Example
263, Step B) and methanesulfonic acid 3-dimethylaminopropyl ester
(Step A) following the procedure described for Example 264.
.sup.1H-NMR (CDCl.sub.3, 200.15 MHz): .delta. 7.14 (d, 2H, J=7.8),
6.83-6.77 (m, 6H), 4.10-4.04 (m, 5H), 3.95-3.89 (m, 4H), 3.37 (s,
3H), 3.16-3.13 (m, 2H), 3.06-2.99 (m, 2H), 2.77 (s, 6H), 2.21-2.15
(m, 4H).
EXAMPLE 269
[2127]
(2S)-3-{4-[3-(4-Carboxymethoxy-phenoxy)-propoxy]-phenyl}-2-methoxy--
propionic acid 537
[2128] Step A
[2129] Methanesulfonyloxy-acetic acid ethyl ester 538
[2130] The title compound was prepared following the procedure
described for methanesulfonic acid 3-dimethylamino-propyl ester
(Example 268, Step A) starting from ethyl glycolate. .sup.1H-NMR
(CDCl.sub.3, 200.15 MHz): .delta. 4.75 (s, 2H), 4.27 (q, 2H,
J=7.3), 3.20 (s, 3H), 1.31 (t, 3H, J=7.3).
[2131] Step B
[2132]
(2S)-3-{4-[3-(4-Carbomethoxy-phenoxy)-propoxy]-phenyl}-2-methoxy-pr-
opionic acid 539
[2133] The title compound was prepared from
(2S)-3-{4-[3-(4-hydroxy-phenox-
y)-propoxy]-phenyl}-2-methoxy-propionic acid ethyl ester (Example
263, Step B) and methane-sulfonyloxy-acetic acid ethyl ester (Step
A) by following the procedure described for Example 264.
.sup.1H-NMR (MeOD, 200.15 MHz): .delta. 67.13 (d, 2H, J=8.6),
6.86-6.81 (m, 6H), 4.57 (s, 2H), 4.15-4.06 (m, 4H), 3.91 (dd, 1H,
F-7.8, 4.8), 3.31 (s, 3H), 2.99 (dd, 1H, J=14.2, 4.6), 2.85 (dd,
1H, J=14.2, 7.5), 2.17 (qn, 2H, J=6.2).
EXAMPLE 270
[2134]
(2S)-3-(4-{3-[4-(1H-Indol-5-phenoxy]-propoxy}-phenyl)-2-methoxy-pro-
pionic acid 540
[2135] Step A
[2136]
(2S)-3-{4-[3-(4-Indol-phenoxy)-propoxy]-phenyl}-2-methoxy-propionic
acid ethyl 541
[2137] (2S)-3-[4-(3-Bromo-propoxy)-phenyl]-2-methoxy-propionic acid
ethyl ester Example 173, Step A) and 4-iodo-phenol were treated
under ester K (Cs.sub.2CO.sub.3) to afford the title compound.
.sup.1H-NMR (CDCl.sub.3, 200.15 MHz): .delta. 7.54 (d, 2H, J=8.9),
7.13 (d, 2H, J=8.6), 6.82 (d, 2H, J=8.9), 6.68 (d, 2H, J=9.1),
4.23-4.08 (m, 6H), 3.90 (dd, 1H, J=7.3, 5.9), 3.35 (s, 3H),
2.97-2.93 (m, 2H), 2.23 (qn, 2H, Jo 6.2), 1.23 (t, 3H, J=7.0).
[2138] Step B
[2139]
(2S)-3-(4-{3-[4-(1H-Indol-5-yl)-phenoxy]-propoxy}-phenyl)-2-methoxy-
-propionic acid ethyl ester 542
[2140] To a stirred mixture of
(2S)-3-{4-[3-(4-iodo-phenoxy)-propoxy]-phen-
yl}-2-methoxy-propionic acid ethyl ester (0.10 mmol, 50 mg) (Step
A), 5-indolyl-boronic acid (0.114 mmol, 18 mg) and powered cesium
carbonate (0.23 mmol, 35 mg) in DME (0.5 mL) was added
Pd(PPh.sub.3).sub.4 (0.003 mmol, 4 mg). The mixture was flushed
with nitrogen and maintained under nitrogen while being heated at
reflux in a 100.degree. C. oil bath. The mixture was stirred for 6
hours, and then cooled to room temperature and diluted with ethyl
acetate and water. The organic layer was dried (Na.sub.2SO.sub.4)
and concentrated. The crude product was purified by chromatography
on silica gel (CH.sub.2Cl.sub.2/EtOAc 96:4) to afford the title
compound .sup.1H-NMR (CDCl.sub.3, 200.15 MHz): .delta. 8.20 (broad
s, 1H), 7.80 (d, 1H, J=0.8), 7.56 (d, 3H, J=8.9), 7.41 (d, 2H,
J=1.6), 7.23 (dd, 1H, J=32, 2.4), 7.15 (d, 3H, J=8.6), 6.99 (d, 2H,
J=8.9), 6.85 (d, 3H, J=8.6), 6.60-6.58 (m, 1H), 4.24-4.11 (m, 8H),
3.92 (dd, 1H, J=7.3, 5.9), 3.35 (s, 4H), 2.98-2.94 (m, 3H), 2.28
(qn, 2H, J=5.9), 1.24 (t, 4H, J=7.3).
[2141] Step C
[2142]
(2S)-3-(4-{3-[4-(1H-Indol-5-yl)-phenoxy]-propoxy}-phenyl)-2-methoxy-
-propionic acid
[2143] The title compound was obtained from
(2S)-3-(4-{3-[4-(1H-indol-5-yl-
)-phenoxy]-propoxy}-phenyl)-2-methoxy-propionic acid ethyl ester
(Step B) by following the standard hydrolysis procedure C (NaOH)
.sup.1H-NMR (CDCl.sub.3, 200.15 MHz): .delta. 8.17 (broad s, 1H),
7.80 (s, 1H), 7.56 (d, 2H, J=8.6), 7.42 (s, 2H), 7.24-7.21 (m, l),
.delta. 7.15 (d, 2H, J=8.6), 6.98 (d, 2H, J=8.6), 6.86 (d, 2H,
J=8.6), 6.59-6.59 (m, 1H), 4.23-4.13 (m, 4H), 3.98 (dd, 1H, J=7.3,
4.3), 3.39 (s, 3H), 3.10 (dd, 1H, J=14.5, 4.0), 2.95 (dd, 1H,
J=14.5, 7.3), 2.27 (qn, 2H, J=6.2).
EXAMPLE 271
[2144]
(2S)-2-Methoxy-3-{4-[3-(4-pyridin-3-yl-phenoxy)-propoxy]-phenyl}-pr-
opionic acid 543
[2145] The title compound was prepared from
(2S)-3-{4-[3-(4-iodo-phenoxy)--
propoxy]-phenyl}-2-methoxy-propionic acid ethyl ester (Example 270,
Step A) and 3-pyridyl boronic acid by following the procedure
described for Example 270 (Steps B and C). .sup.1H-NMR (MeOD,
300.15 ME): .delta. 8.76 (s, 1H), 8.46 (s, 1H), 8.05 (d, 1H,
J=8.1), 7.60 (d, 2H, J=8.7), 7.49 (dd, 1H, J=7.7, 4.8), 7.19 (d,
2H, J=8.5), 7.09 (d, 2H, J=8.7), 6.85 (d, 2H, J=8.5), 4.24 (t, 2H,
J=6.1), 4.17 (t, 2H, J=6.3), 3.74 (dd, 1H, J=8.7, 3.8), 3.27 (s,
3H), 2.97 (dd, 1H, J=14.3, 3.8), 2.81 (dd, 1H, J=14.1, 8.5), 2.26
(qn, 2H, J=6.0).
EXAMPLE 272
[2146]
(2S)-2-Methoxy-3-{4-[3-(4-pyridin-4-yl-phenoxy)-phenoxy]-phenyl}-pr-
opionic acid 544
[2147] The title compound was prepared from
(2S)-3-{4-[3-(4-iodo-phenoxy)--
propoxy]-phenyl}-2-methoxy-propionic acid ethyl ester (Example 270,
Step A) and 4-pyridyl boronic acid by following the procedure
described for Example 270 (Steps B and C). .sup.1H-NMR (CDCl.sub.3,
200.15 MHz): .delta. 8.67-8.65 (m, 2H), 8.16 (d, 2H, J=6.6), 7.90
(d, 2H, J=8.8), 7.16-7.09 (, 4H), 6.82 (C, 2H, J=8.8), 4.26 (t, 2H,
J=6.2), 4.13 (t, 2H, J=6.2), 3.90 (dd, 1H, J=7.7, 4.8), 2.97 (dd,
1H, J=143, 5.1), 2.83 (dd, 1H, J=14.3, 7.7), 2.24 (qn, 2H,
J=5.9).
EXAMPLE 273
[2148]
(2S)-2-Methoxy-3-{4-[3-(4-quinolin-8-yl-phenoxy)-propoxy]-phenyl}-p-
ropionic acid 545
[2149] The title compound was prepared from
(2S)-3-{4-[3-(4-iodo-phenoxy)--
propoxy]-phenyl}-2-methoxy-propionic acid ethyl ester (Example 270,
Step A) and 8-quinoline boronic acid by following the procedure
described for Example 270 (Steps B and C). .sup.1H-NMR (MeOD,
300.15 MHz): .delta. 8.82 (d, 1H, J=2.6), 8.39 (d, 1H, J=8.1), 7.92
(d, 1H, J=7.9), 7.74-7.63 (m, 2H), 7.58-7.51 (m, 3H), 7.18 (d, 2H,
J=8.5), 7.08 (d, 2H, J=8.7), 6.88 (d, 2H, J=8.7), 4.28 (t, 2H,
J=6.0), 4.20 (t, 2H, J=6.3), 3.90-3.80 (m, 1H), 3.30 (s, 3H),
3.04-2.84 (m, 2H), 2.29 (qn, 2H, J=6.3).
EXAMPLE 274
[2150]
(2S)-3-{4-[3-(4'-Cyano-biphenyl-4-yloxy)-propoxy]-phenyl}-2-methoxy-
-propionic acid 546
[2151] Step A
[2152]
(2S)-3-{4-[3-(4'-Cyano-biphenyl-4-yloxy)-propoxy]-phenyl}-2-methoxy-
-propionic acid ethyl ester 547
[2153] (2S)-3-[4-(3-Bromo-propoxy)-phenyl]-2-methoxy-propionic acid
ethyl ester (Example 173, Step A) and
4'-hydroxy-4-biphenylcarbonitrile were treated under Mitsunobu
standard conditions B (DIAD, toluene) to give the title compound.
.sup.1H-NMR (CDCl.sub.3, 200.15 MHz): .delta. 7.71-7.60 (m, 4H),
7.52 (d, 2H, J=8.9), 7.14 (d, 2H, J=8.9), 7.00 (d, 2H, f-8.9), 6.83
(d, 2H, J=8.6), 4.24-4.12 (m, 6H), 3.90 (dd, 1H, J=7.3, 5.9), 3.34
(s, 3H), 2.97-2.93 (m, 2H), 2.27 (qn, 2H, J=6.2), 1.23 (t, 3H,
J=7.3).
[2154] Step B
[2155]
(2S)-3-{4-[3-(4'-Cyano-biphenyl-4-yloxy)-propoxy]-phenyl}-2-methoxy-
-propionic acid
[2156] The title compound was prepared from
(2)-3-{4-[3-(4'-cyano-biphenyl-
-4-yloxy)-propoxy]-phenyl}-2-methoxy-propionic acid ethyl ester
(Step A) via the standard hydrolysis procedure C (NaOH).
.sup.1H-NMR (MeOD, 300.15 MHz): .delta. 7.77 (s, 4H), 7.64 (d, 2H,
J=8.7), 7.18 (d, 2H, J=8.5), 7.07 (d, 2H, J=8.7), 6.86 (d, 2H,
J=8.3), 4.24 (t, 2H, J=6.3), 4.17 (t, 2H, J=6.3), 3.84-3.74 (m,
1H), 3.03-2.81 (m, 2H), 2.26 (qn, 2H, J=6.0).
EXAMPLE 275
[2157]
(2S)-2-Methoxy-3-(4-{3-[4'-(1H-tetrazol-5-yl)biphenyl-4-yloxy]-prop-
oxy}-phenyl)-propionic acid 548
[2158] Step A
[2159]
(2S)-2-Methoxy-3-(4-{3-[4'-(1H-tetrazol-5-yl)biphenyl-4-yloxy]-prop-
oxy}-phenyl)-propionic acid ethyl ester 549
[2160] Azidotributyltin (0.72 mmol, 0.2 mL) was added to a solution
of
(2S)-3-{4-[3-(4'-cyano-biphenyl-4-yloxy)-propoxy]-phenyl}-2-methoxy-propi-
onic acid ethyl ester (0.36 mmol, 0.17 g) (Example 274, Step A) in
toluene (1 mL). The mixture was heated at 60.degree. C. for 48
hours. The mixture was allowed to reach room temperature and 1N HCl
was added. The mixture was heated at reflux for 24 additional
hours. Upon cooling, water was added and the aqueous phase was
extracted with ethyl acetate. The organic layer was dried
(Na.sub.2SO.sub.4), filtered and evaporated. The crude product was
purified by chromatography on silica gel (hexanes/ethyl
acetate/acetic acid 3.2:10%) to afford the title product.
.sup.1H-NMR (CDCl.sub.3, 200.15 MHz): .delta. 8.12 (d, 2H, J=8.3),
7.65 (d, 2H, J=8.6), 7.51 (d, 2H, J=8.9), 7.11 (d, 2H, J=8.6), 6.95
(d, 2H, J=8.6), 6.79 (d, 2H, 8.6), 4.25-4.06 (m, 7H), 3.97 (dd, 1H,
J=7.0, 5.4), 3.37 (s, 3H), 2.99-2.96 (m, 2H), 2.22 (qn, 2H, J=5.9),
1.25 (t, 3H, J=7.2).
[2161] Step B
[2162]
(2S)-2-Methoxy-3-(4-{3-[4'-(1H-tetrazol-5-yl)biphenyl-4-yloxy]-prop-
oxy}-phenyl)-propionic acid
[2163] The title compound was prepared from
(2S)-2-methoxy-3-(4-{3-[4'-(1H-
-tetrazol-5-yl)biphenyl-4-yloxy]-propoxy}-phenyl)-propionic acid
ethyl ester (Step A) via the standard hydrolysis procedure C
(NaOH). .sup.1H-NMR (MeOD, 300.15 M 8): 58.09 (d, 2H, J=8.3), 7.70
(d, 2H, J=8.3), 7.62 (d, 2H, J=8.7), 7.18 (d, 2H, J=8.5), 7.05 (d,
2H, J=8.7), 6.86 (d, 2H, J=8.7), 4.23 (t, 2H, J=6.0), 4.17 (t, 2H,
J=6.1), 3.83 (dd, 1H, J=8.3, 4.2), 3.36 (s, 3H), 2.99 (dd, 1H,
J=14.1, 4.0), 2.84 (dd, 1H, J=13.9, 8.1), 2.26 (qn, 2H, J=6.3).
EXAMPLE 276
[2164]
(2S)-3-{4-[3-(4-Imidazol-1-yl-phenoxy)-propoxy]-phenyl}-2-methoxy-p-
ropionic acid 550
[2165] 3-[4-(3-Bromo-propoxy)-phenyl]-2-methoxy-propionic acid
ethyl ester (Example 173, Step A) and 4-(imidazol-1-yl)phenol were
treated under ester J to give the title compound. .sup.1H-NMR
(CDCl.sub.3, 200.15 MHz): .delta. 8.11 (s, 1H), 7.31-7.16 (m, 7H),
6.99 (d, 2H, J=8.9), 6.82 (d, 2H, J=8.6), 4.19 (t, 2H, J=6.2), 4.12
(t, 2H, J=5.9), 3.95 (dd, 1H, J=7.3, 4.8), 3.39 (s, 3H), 3.08 (dd,
1H, J=14.4, 4.8), 2.96 (dd, 1H, J=14.2, 7.6), 2.26 (qn, 2H,
J=5.9).
EXAMPLE 277
[2166]
(2S)-3-(4-{3-[4-(1,3-Dioxo-1,3-dihydro-isoindol-2-yl)-phenoxy]-prop-
oxy}-phenyl)-2-methoxy-propionic acid 551
[2167] The title compound was obtained from
(2)-3-[4-(3-Bromo-propoxy)-phe- nyl]-2-methoxy-propionic acid ethyl
ester (Example 173, Step A) and N-(4-hydroxyphenyl) phtalimide by
following the procedure described for Example 276. .sup.1H-NMR
(CDCl.sub.3, 300.15 MHz): .delta. 7.97-7.92 (m, 2H), 7.81-7.77 (m,
2H), 7.32 (d, 2H, J=8.9), 7.15 (d, 2H, J=8.5), 7.02 (d, 2H, J=8.9),
6.85 (d, 2H, J=8.5), 4.20 (t, 2H, J=6.0), 4.16 (t, 2H, J=6.0), 3.99
(dd, 131, 7.3, 4.4), 3.41 (s, 3H), 3.11 (dd, 1H, J=14.3, 4.4), 2.97
(dd, 1H, J=14.3, 7.1), 2.27 (qn, 2H, J=6.0).
EXAMPLE 278
[2168]
(2S)-3-(4-{3-[4-(4-Acetyl-piperazin-1-yl)-phenoxy]-propoxy}-phenyl)-
-2-methoxy-propionic acid 552
[2169] The title compound was obtained from
(2S)-3-[4-(3-Bromo-propoxy)-ph- enyl]-2-methoxy-propionic acid
ethyl ester (Example 173, Step A) and
1-acetyl-4-(4-hydroxyphenyl)piperazine by following the procedure
described for Example 276. .sup.1H-NMR (CDCl.sub.3, 300.15 MHz):
.delta. 7.14 (d, 2H, J=8.5), 6.90-6.80 (m, 5H), 4.15-4.09 (m, 3H),
3.98 (dd, 1H, J=6.7, 4.9), 3.79-3.76 (m, 2H), 3.63-3.60 (m, 2H),
3.40 (s, 3H), 3.11-2.93 (m, 6H), 2.14 (s, 3H).
EXAMPLE 279
[2170]
(2S)-2-Methoxy-3-{4-[3-(4-piperazin-1-yl-phenoxy)-propoxy]-phenyl}--
propionic acid 553
[2171] Step A
[2172]
(2S)-2-Methoxy-3-{4-[3-(4-piperazin-1-yl-phenoxy)-propoxy]-phenyl}--
propionic acid ethyl ester 554
[2173] 3-[4-(3-Bromo-propoxy)-phenyl]-2-methoxy-propionic acid
ethyl ester (Example 173, Step A) and
1-(4-hydroxyphenyl)-piperazine were treated under ester K to give
the title compound. .sup.1H-NMR (CDCl.sub.3, 200.15 MHz): .delta.
8.01 (s, 1H), 7.13 (d, 2H, J=8.6), 6.88-6.75 (m, 6H), 4.30 (t, 2H,
J=6.4), 4.17 (q, 2H, J=7.0), 4.02 (t, 2H, J=5.9), 3.94-3.87 (m,
1H), 3.64-3.60 (m, 4H), 3.34 (s, 3H), 2.98-2.96 (m, 4H), 2.18-2.04
(m, 2H), 1.23 (t, 3H, J=7.3).
[2174] Step B
[2175]
(2S)-2-Methoxy-3-{4-[3-(4-piperazin-1-yl-phenoxy)-propoxy]-phenyl}--
propionic acid
[2176] The title compound was prepared from
(2S)-2-methoxy-3-{4-[3-(4-pipe-
razin-1-yl-phenoxy)-propoxy]-phenyl}-propionic acid ethyl ester
(Step A) by standard hydrolysis procedure C (NaOH). .sup.1H-NMR
(MeOD 300.15 MHz): 37.18 (d, 2H, j 8.5), 6.89-6.83 (m, 4H), 6.72
(d, 2H, J=9.1), 4.30 (t, 2H, J=6.3), 4.07 (t, 2H, J=6.1), 3.86-3.82
(m, 1H), 3.62-3.59 (m, 4H), 3.36 (s, 3H), 3.07-2.83 (m, 6H), 2.12
(qn, 2H, J=6.3).
EXAMPLE 280
[2177]
(2S)-2-Methoxy-3-{4-[3-(4-morpholin-4-yl-phenoxy)-propoxy]-phenyl}--
propionic acid 555
[2178] Step A
[2179]
(2S)-2-Methoxy-3-{4-[3-(4-morpholin-4-yl-phenoxy)-propoxy]-phenyl}--
propionic acid ethyl ester 556
[2180] A mixture of
(2S)-3-{4-[3-(4-iodo-phenoxy)-propoxy]-phenyl}-2-metho-
xy-propionic acid ethyl ester (1.03 mmol, 0.5 g), morpholine (1.24
mmol, 0.11 mL), Pd(OAc), (0.05 mmol, 12 mg),
2,2'-bis(diphenylphsphino)-1,1'-bi- naphthyl (0.08 mmol, 48 mg) and
cesium carbonate (1.45 mmol, 471 mg) in DMF (2 mL) was heated at
110.degree. C. for 14 hours. The mixture was purified through a
silica gel column (hexanes/ethyl acetate 7:3) to afford the title
compound. .sup.1H-NMR (CDCl.sub.3, 200.15 MHz): .delta. 7.11 (d,
2H, J=8.8), 6.85 (broad s, 2H), 6.80 (d, 4H, J=8.8), 4.21-4.04 (m,
6H), 3.91-3.80 (m, 5H), 3.32 (s, 3H), 3.10-2.95 (m, 4H), 2.94-2.91
(m, 2H), 2.20 (qn, 2H, J=5.9), 1.23 (t, 3H, J=7.2).
[2181]
(2S)-2-Methoxy-3-{4-[3-(4-morpholin-4-yl-phenoxy)-propoxy]-phenyl}--
propionic acid
[2182] The title compound was prepared from
(2S)-2'-ethoxy-3-{4-[3-(4-morp-
holin-4-yl-phenoxy)-propoxy]-phenyl}-propionic acid ethyl ester
(Step A) by standard hydrolysis procedure C (NaOH). .sup.1H-NMR
(CDCl.sub.3, 200.15 MHz): .delta. 9.90 (s, 1H), 7.30 (d, 2H,
J=9.1), 7.10 (d, 2H, J=8.4), 6.91 (d, 2H, J=9.1), 6.75 (d, 2H,
J=8.8), 4.18-3.90 (m, 9H), 3.43-3.33 (m, 7H), 3.02 (dd, 1H, J=14.3,
4.8), 2.90 (dd, 1H, J=14.3, 7.0), 2.18 (qn, 2H, J=5.9).
EXAMPLE 281
[2183]
(2S)-3-{4-[3-(Biphenyl-4-yloxy)-propoxy]-2-chloro-phenyl}-2-ethoxy--
propionic acid 557
[2184] Step A
[2185]
3-[4-(3-(Biphenyl-4-yloxy)-propoxy]-2-chloro-phenyl}-2-hydroxy-prop-
ionic acid 558
[2186] Boron tribromide (0.03 mmol, 0.03 mL) was added to a
solution of
3-{4-[3-(biphenyl-4-yloxy)-propoxy]-2-chloro-phenyl}-2-methoxy-propionic
acid (0.06 mmol, 25.5 mg) (Example 191) in CH.sub.2Cl.sub.2 (0.4
mL) at -78.degree. C. The mixture was warmed to temperature
gradually and stirred for 12 hours. The solvent was concentrated to
dryness to afford the title compound. .sup.1H-NMR (CDCl.sub.3,
200.15 MHz): .delta. 7.56-7.18 (m, 8H), 6.99-6.95 (m, 3H),
6.79-6.75 (m, 1H), 4.58-4.42 (m, 1H), 4.25-4.12 (m, 4H), 3.34-2.92
(m, 2H), 2.30-2.22 (m, 2H).
[2187] Step B
[2188]
3-{4-[3-(Biphenyl-4-yloxy)-propoxy]-2-chloro-phenyl}-2-ethoxy-propi-
onic acid
[2189] Ethyl iodide (0.6 mmol, 0.05 mL) was added to a solution of
3-{4-[3-(biphenyl-4-yloxy)-propoxy]-2-chloro-phenyl}-2-hydroxy-propionic
acid (Step A) and Ag.sub.2O (0.09 mmol, 21 mg) in DMF (0.5 mL). The
mixture was heated at 50.degree. C. for 24 hours. The mixture was
warmed to room temperature, and 1N HCl was added until pH 3. The
aqueous phase was extracted with ethyl acetate (3.times.10 mL). The
combined organic layers were dried (Na.sub.2SO.sub.4), filtered and
evaporated. The crude was purified by chromatography on silica gel
(CH.sub.2Cl.sub.2) to afford the title compound. .sup.1H-NMR
(CDCl.sub.3, 300.15 MHz): .delta. 7.56-7.51 (m, 4H), 7.44-7.39 (m,
2H), 7.30 (t, 1H, J=7.3), 7.20 (d, 1H, J=8.5), 6.99 (d, 2H, J=8.7),
6.95 (d, 1H, J=2.4), 6.77 (dd, 1H, J=8.5, 2.4), 4.21-4.13 (m, 5H),
3.64-3.54 (m, 1H), 3.44-3.34 (m, 1H), 3.29 (dd, 1H, J=14.1, 4.2),
3.01 (dd, 1H, J=14.1, 8.7), 2.28 (qn, 2H, J=6.0), 1.12 (t, 3H,
J=6.9).
EXAMPLE 282
[2190]
3-{4-[3-(4-Benzoyl-phenoxy)-propoxy]-2-chloro-phenyl}-2-ethoxy-prop-
ionic acid 559
[2191] The title compound was prepared from
3-{4-[3-(4-benzoyl-phenoxy)-pr-
opoxy]-2-chloro-phenyl}-2-methoxy-propionic acid (Example 193) by
following the same procedure as in Example 281 (Steps A and B).
.sup.1H-NMR (CDCl.sub.3, 300.15 MHz): .delta. 7.82 (d, 2H, J=8.7),
7.76 (d, 2H, J=8.1), 7.61-7.55 (m, 1H), 7.50-7.45 (m, 2H), 7.18 (d,
1H, J=8.5), 6.99-6.95 (m, 3H), 6.77 (dd, 1H, J=8.5, 2.4), 4.25 (t,
2H, J=5.9), 4.17-4.14 (m, 3H), 3.61-3.38 (m, 2H), 3.29 (dd, 1H,
J=14.1, 4.9), 3.02 (dd, 1H, J=14.1, 8.1), 2.31 (qn, 2H, J=5.9),
1.14 (t, 3H, J=7.1).
EXAMPLE 283
[2192]
(2S)-3-{4-[2-(biphenyl-4-yloxy)-ethoxy]-phenyl}-2-methoxy-propionic
acid 560
[2193] Step 1: (2S)-3-(4-hydroxy-phenyl)-2-methoxy-propionic acid
ethyl ester 561
[2194] The compound of
(2S)-3-(4-hydroxy-phenyl)-2-methoxy-propionic acid (5.1 mmol) was
dissolved in 50 ml of ethanol and 0.3 ml (5.6 mmol) of sulfuric
acid was added. The mixture was stirred at room temperature for 18
hours and then concentrated. The mixture was diluted with water (55
ml) and NaHCO.sub.3 was added (310 mg, 3.7 mmol). This mixture was
extracted with ethyl acetate (4.times.20 mL), and the combined
organic layers were dried (gSO.sub.4) and then concentrated to
produce a yellow oil. .sup.1H-NMR (CDCl.sub.3, 200.15 MHz): 7.07
(d, 2H, J=8.6), 6.72 (d, 2H, J=8.6), 5.42 (br s, 1H), 4.18 (q, 2H,
J=7.3), 3.92 (dd, 1H, J=6.7, 5.9), 3.36 (s, 3H), 2.95 (d, 2H,
J=6.7), 1.23 (t, 3H, J=7.3).
[2195] Step 2:
(2S)-3-[4-(2-bromo-ethoxy)-phenyl]-2-methoxy-propionic acid ethyl
ester 562
[2196] A mixture containing
(2S)-3-(4-hydroxy-phenyl)-2-methoxy-propionic acid ethyl ester
obtained in Step 1 (0.223 mol, 50 mg), potassium carbonate (0.446
mol, 50 mg), magnesium sulfate (powdered, 50 mg, 1 gig), ethylene
dibromide (3.35 mol. 628 mg) and EtOH (25 mL) was heated at reflux
(78-76.degree. C.) for 24 hours and cool to room temperature. The
mixture was heated again to reflux (76.5-77.degree. C.) and 2 mL of
ethylene dibromide was added. The mixture was heated for another 12
hours at 79.5-80.1.degree. C. and then cooled to room temperature
and vacuum filtered. The filtrate was concentrated under vacuum,
and the residue was purified by column chromatography (silica gel,
hexanes/ethyl acetate 6:1, Rf 027) to produce a colorless oil. MS
(ES) for C.sub.14H.sub.19BrO.sub.4 [M+Na].sup.+: 353.0.
[2197] Step 3:
(2S)-3-{4-[2-(biphenyl-4-yloxy)-ethoxy]-phenyl}-2-methoxy-p-
ropionic acid 563
[2198] A solution of biphenyl-4-ol (0.39 mmol, 68 mg) in 10 ml of
DMF in was treated with
(2S)-3-[4-(2-bromo-ethoxy)-phenyl]-2-methoxy-propionic acid ethyl
ester obtained in Step 2 (0.33 mmol, 100 mg) and cesium carbonate
(0.66 mmol, 214 mg) in a round bottom flask. The reactants were
filtered and was washed with DMF several times and the solvent was
evaporated under vacuo. The residue was reconstituted in a mixture
of ethanol (20 ml) and NaOH (1M) (8 ml), and then stirred at room
temperature until TLC indicated the disappearance of starting
material. Ethanol was removed under vacuum, and the aqueous
solution was diluted with 20 ml of brine and washed with diethyl
ether (3.times.15 mL). The aqueous phase was acidified with
[2199] 1N HCl (pH 1-2) and extracted with ethyl acetate (3.times.15
mL). The organic layer was dried (MgSO.sub.4) and concentrated
under vacuum to yield the title compound. MS (ES) for
C.sub.24H.sub.24O.sub.5 [M+Na].sup.+: 415.4.
EXAMPLE 284
[2200]
(2S)-2-methoxy-3-{4-[3-(3-trifluoromethyl-phenoxy)-propoxy]-phenyl}-
-propionic acid 564
[2201] Step 1: 3-bromopropan-1-ol
[2202] The compound of 1,3-propanodiol (10.26 g, 134.8 mmol) was
dissolved in benzene (150 mL), and HBr 48% (16.84 mL) was added.
The mixture was refluxed under aceotropic removal of water for 24
hours. The solvent was distilled at atmospheric pressure, and the
residue was diluted with ether and (150 mL) and washed with water
(3.times.50) mL. The organic layer was dried over MgSO.sub.4 and
concentrated to afford a yellowish oil. .sup.1H-NMR (CDCl.sub.3,
200.15 MHz): 3.80 (t, 2H, J=6.4), 3.54 (t, 2H, J=6.5), 2.10 (qn,
2H, J=6.4).
[2203] Step 2:
(2S)-3-[4-(3-bromo-propoxy)-phenyl]-2-methoxy-propionic acid ethyl
ester 565
[2204] A solution of triphenylphosphine (4.77 mmol, 1250 mg) in 50
mL of dry toluene was treated at 0.degree. C. with
diisopropilazodicarboxylate (4.77 mmol, 964.5 mg) and stirred for
about 20 un A solution of
(2S)-3-(4-hydroxy-phenyl)-2-methoxy-propionic acid ethyl ester
(Example 283, Step 1) (4.46 mmol, 1000 mg) and 3-bromo-propan-1-ol
(4.77 mmol, 663 mg) in 10 mL of dry THF was added, and the mixture
was stirred at room temperature overnight. The mixture was
concentrated to dryness under vacuum and purified by silica gel
chromatography (silica gel, hexanes/ethyl acetate 6:1). The
fraction with Rf 0.4 corresponding to the coupled compound was
combined and concentrated to dryness to afford a yellow oil. MS
(ES) for C.sub.15H.sub.21BrO.sub.4 [M+Na].sup.+: 367.2.
[2205] Step 3:
(2S)-2-methoxy-3-{4-[3-(3-trifluoromethyl-phenoxy)-propoxy]-
-phenyl}-propionic acid 566
[2206] The title compound was prepared from
(2S)-3-[4-(3-bromo-propoxy)-ph- enyl]-2-methoxy-propionic acid
ethyl ester (Example 284, Step 2) and 3-trifluoromethyl-phenol via
the same procedure used for the preparation of
(2S)-3-{4-[2-(Biphenyl-4-yloxy)-ethoxy]-phenyl}-2-methoxy-propionic
acid (Example 283, Step 3) to produce a yellow solid.
[2207] MS (ES) for C.sub.50H.sub.21F.sub.3O.sub.5
[M+NH.sub.4].sup.+: 421.4.
EXAMPLE 285
[2208] (2S)-2-methoxy-3-[4-(3-phenoxy-propoxy)-phenyl]-propionic
acid 567
[2209] A solution of
(2S)-3-[4-(3-bromo-propoxy)-phenyl]-2-methoxy-propion- ic acid
ethyl ester (Example 0.284, Step 2) (0.1 mmol, 32 mg) in 0.7 ml of
DM in a 16.times.100 mm tube was treated with phenol (0.15 mmol, 15
mg), cesium carbonate (0.3 mmol, 95 mg). The mixture was stirred at
room temperature overnight and the reactants were filtered and
washed with DMF a several times. The solvent was evaporated under
vacuum, and the residue was reconstituted in a mixture of ethanol
(2 ml) and NaOH (1M, 1 ml), which was stirred at room temperature
until temperature until reaction was completed by HPLC-MS. Upon
completion, HCl (1M) was added pH=3) and the solvents were
eliminated under vacuum. The residue was reconstituted in
CH.sub.2Cl.sub.2/H.sub.2O and filtered through a hidrofobic
syringer. The organic layer was separated, concentrated and
purified by HPLC-MS to afford the title compound as a colorless
oil. MS (ES) for C.sub.19H.sub.22O.sub.5 [M+NH.sub.4].sup.+:
348.4.
EXAMPLE 286
[2210]
(2S)-3-{4-[3-(biphenyl-3-yloxy)-propoxy]-phenyl}-2-methoxy-propioni-
c acid 568
[2211] The title compound was prepared from
(2S)-3-[4-(3-bromo-propoxy)-ph- enyl]-2-methoxy-propionic acid
ethyl ester (Example 284, Step 2): and biphenyl-3-ol via the same
procedure used for the preparation of
(2S)-2-methoxy-3-[4-(3-phenoxy-propoxy)-phenyl]-propionic acid
(Example 285, Step 1), to produce a colorless oil. MS (ES) for
C.sub.25H.sub.25O.sub.5 [M+Na]+429.4.
EXAMPLE 287
[2212]
(2S)-2-methoxy-3-{4-[3-(2-methyl-benzothiazol-5-yloxy)-propoxy]-phe-
nyl}-propionic acid 569
[2213] The title compound was prepared from
(2S)-3-[4-(3-bromo-propoxy)-ph- enyl]-2-methoxy-propionic acid
ethyl ester (Example 284, Step 2) and 2-methyl-benzothiazol-5-ol
via the same procedure used for the preparation of
(2S)-2-methoxy-3-[4-(3-phenoxy-propoxy)-phenyl]-propionic acid
Example 285, Step 1), to produce a colorless oil.
[2214] MS (ES) for C.sub.2H.sub.23NO.sub.5S [M+H].sup.+: 402.4.
EXAMPLE 288
[2215]
(2S)-2-methoxy-3-{4-[3-(3-morpholin-4-yl-phenoxy)-propoxy]-phenyl}--
propionic acid 570
[2216] The title compound was prepared from
(2S)-3-[4-(3-bromo-propoxy)-ph- enyl]-2-methoxy-propionic acid
ethyl ester (Example 284, Step 2) and 3-Morpholin-4-yl-phenol via
the same procedure used for the preparation of
(2S)-2-methoxy-3-[4-(43-phenoxy-propoxy)-phenyl]-propionic acid
(Example 285, Step 1), to produce a colorless oil.
[2217] MS (ES) for C.sub.23H.sub.29NO.sub.6 [M+H].sup.+: 416.4.
EXAMPLE 289
[2218]
(2S)-2-methoxy-3-{4-[3-(5,6,7,8-tetrahydro-naphthalen-2-yloxy)-prop-
oxy]-phenyl}-propionic acid 571
[2219] The title compound was prepared from
(2S)-3-[4-(3-bromo-propoxy)-ph- enyl]-2-methoxy-propionic acid
ethyl ester (Example 284, Step 2) and
5,6,7,8-tetrahydro-naphthalen-2-ol via the same procedure used for
the: preparation of
(2S)-3-{4-[2-(biphenyl-4-yloxy)-ethoxy]-phenyl}-2-methoxy--
propionic acid (Example 283, Step 3), to produce a white solid.
[2220] MS (ES) for C.sub.23H.sub.28O.sub.5 [M+Na].sup.+: 402.4.
EXAMPLE 290
[2221]
2-methoxy-3-{4-[2-(4-phenoxy-phenoxy)-ethoxy]-phenyl}-propionic
acid 572
[2222] The title compound was prepared from
(2S)-3-[4-(2-bromo-ethoxy)-phe- nyl]-2-methoxy-propionic acid ethyl
ester (Example 283, Step 2) and 4-phenoxy-phenol via the same
procedure used for the preparation of
(2S)-3-{4-[2-(biphenyl-4-yloxy)-ethoxy]-phenyl}-2-methoxy-propionic
acid (Example 283, Step 3) to produce a white solid.
[2223] MS (ES) for C.sub.24H.sub.24O.sub.6 [M+NH.sub.4].sup.+:
426.0.
EXAMPLE 291
[2224]
3-{3-[3-(biphenyl-4-yloxy)-propoxy]-phenyl}-2-methoxy-propionic
acid (isomer 1) 573
[2225] Step 1: 3-(3-benzyloxy-phenyl)-3-hydroxy-2-methoxy-propionic
acid methyl ester 574
[2226] Sodium trimethylsilylamide 1M in THF (20.73 mL, 20.73 mmol)
was added to a 2-neck round bottom flask under nitrogen. The flask
was placed in an acetone bath cooled to about -78.degree. C. A
solution of methyl 2-methoxyacetate (2.34 mL, 23.55 mmol) and
3-benzyloxybenzaldehyde (4.0 g, 18.85 mmol) in dry THF (24 mL) was
added dropwise via cannula over 10 minutes. The mixture was stirred
at -78.degree. C. for 3 hours. HPLC-MS showed the presence of
starting aldehyde at this time. Additional 10 mL of NaHDMS were
added, and the mixture was stirred for another hour, and then HCl
3N (50 mL) was added to the mixture at -78.degree. C. The bath was
removed, and the mixture was extracted with diethyl ether
(4.times.50 mL). The combined organic layers were dried over
MgSO.sub.4 and concentrated to afford an oil that was purified by
chromatography (silica gel, hexanes/ethyl acetate 3:1). Rf. 0.13.
(two isomers) .sup.1H-NMR (CDCl.sub.3, 200.15 MHz): 7.45-7.22 (m,
12H), 7.05-6.89 (m, 6H), 5.07 (d, 4H, J=1.1), 4.93 (dd, 2H, J=11.8,
5.9), 3.97 (d, 1H, J=5.6), 3.89 (d, 1H, J=5.4), 3.67 (s, 3H), 3.65
(s, 3H), 3.40 (s, 3H), 3.37 (s, 3H), 2.92 (br s, 1H), 2.83 (br s,
1H).
[2227] Step 2: 3-(3-benzyloxy-phenyl)-2-methoxy-acrylic acid methyl
ester 575
[2228] The compounds of
3-(3-benzyloxy-phenyl)-3-hydroxy-2-methoxy-propion- ic acid methyl
ester (Example 291, Step 1) (4.06 g, 12.84 mmol), triethylamine
(7.15 mL, 51.33 mmol) and 4-(N,N-dimethylamino)pyridine (0.157 g,
128 mmol) were dissolved in dichloromethane (20 mL) in a round
bottom flask and then cooled to 0.degree. C. under ice bath. Mesyl
chloride (1.093 mL, 14.1 mmol) was added dropwise via syringe, and
the mixture was stirred at room temperature until no starting aldol
is observed by HPLC-MS (4 days, 0.2 additional mL of MsCl were
added each day). The mixture was diluted with 200 mL of diethyl
ether, washed with HCl (1N, 3.times.40 mL) and 40 mL of brine, and
dried over MgSO.sub.4 Concentration of the mixture afforded 3.96 g.
of a 2.5:1 mixture of the acrylate and a single isomer of the
mesylate intermediate which was directly used in the next Step.
.sup.1H-NMR (CDCl.sub.3, 200.15 MHz): 7.46-7.26 (m, 8H), 6.99-6.93
(m, 1H), 5.10 (s, 2H), 3.85 (s, 3H), 3.72 (s, 3H).
[2229] Step 3: 3-(3-benzyloxy-phenyl)-2-methoxy-propionic acid
methyl ester 576
[2230] A solution of 3-(3-benzyloxy-phenyl)-2-methoxy-acrylic acid
methyl ester (Example 291, Step 2) (3.96 g) in methanol (10 mL) was
placed in a round bottom flask equipped with a reflux condenser.
The mixture was cooled to 0.degree. C. and Mg turnings (6.45 g)
were added. The mixture was initially stirred vigorously and then
further stirred at room temperature for about an hour. The solvent
was evaporated under vacuum, and 100 mL of diethyl ether were added
to the resulting solid. HCl (3N, 100 mL) was added and the solution
was stirred for one minute. The organic layer was separated from
the slurry, and 100 mL of diethyl ether and HCl (3N, 100 mL) were
added to the remaining slurry. The procedure was repeated until the
entire solid was dissolved. The combined ethereal extracts were
washed with brine and dried over MgSO.sub.4. Concentration of the
mixture afforded a yellow oil which was about 90% pure bye
.sup.1H-NMR (CDCl.sub.3, 200.15 MHz): 7.45-7.17 (m, 6H), 6.88-6.81
(m, 3H), 5.05 (s, 2H), 3.97 (dd, 1H, J=7.3, 5.4), 3.72 (s, 3H),
3.34 (s, 3H), 3.00 (d, 1H, J=5.1), 2.99 (d, 1H, J=7.8).
[2231] Step 4: 3-(3-hydroxy-phenyl)-2-methoxy-propionic acid methyl
ester 577
[2232] The compounds of 3-(3-benzyloxy-phenyl)-2-methoxy-propionic
acid methyl ester (Example 291, Step 3) (3.15 g, 10.49 mmol) and Pd
10% on activated carbon (0.558 g, 0.524 mmol) were placed in a 250
ml round bottom flask equipped with a magnetic stirring bar. 100 mL
of methanol was added, and hydrogen was bubbled through the
solution for 10 minutes. The flask was sealed with a rubber septum,
and a balloon containing 250 mL of hydrogen was connected to the
flask through a needle. The mixture was stirred at room temperature
for 5 hours and then concentrated to dryness under vacuum. The
residue was taken up in ethyl acetate and filtered through a pad of
celite. Concentration of the mixture afforded an oil, .sup.1H-NMR
(CDCl.sub.3, 200.15 MHz): 7.15 (dt, 1H, J=1.1, 7.0), 6.79-6.68 (m,
3H), 5.27 (br s, 1H), 3.98 (dd, 1H, J=7.5, 5.6), 3.73 (s, 3H), 3.35
(s, 3H), 2.97 (d, 1H, J=3.8), 2.97 (d, 1H, J=9.1).
[2233] Step 5: [1,3,2]dioxathiane 2,2-dioxide 578
[2234] Thionyl chloride (36 mL, 491 mmol) was, added to a solution
of 1,3-propanodiol (30 g, 394 mmol) in CCl.sub.4 (278 mL) via
syringe. The mixture was heated at reflux for 1.5 hours and cooled
to 0.degree. C. to evaporate the solvent under vacuum. The residue
was dissolved in a mixture of CCl.sub.4/CH.sub.3CN/H.sub.2O
(2:2:3=500 mL) and cooled to 0.degree. C. Ruthenium trichloride
trihydrate (0.556 g, 2.68 mmol) was added followed by addition of
solid NaIO.sub.4 (14.35 g, 197 mmol). The mixture was stirred at
room temperature for 1 hour and then H.sub.2O (1 L) was added. The
aqueous phase was extracted with diethyl ether (4.times.300 mL).
The combined organic layers were washed with brine (2.times.100
mL), dried (MgSO.sub.4), and filtered through a pad of silica gel
to remove the ruthenium salts. The solvent was evaporated, and
hexanes (200 mL) was added to the resulting oil. After cooling, a
gray solid was precipitated, which was filtered and washed with
hexanes. Recrystallization from hexanes/ether yielded a white
crystaline solid. .sup.1H-NMR (200.15 MHz, CDCl.sub.3): d 4.73 (t,
4H, J=5.6), 2.13 (qn, 2H, J=5.6).
[2235] Step 6: 3-(biphenyl-4-yloxy)-propan-1-ol 579
[2236] A solution of 4-phenylphenol (4.9 g, 29.0 mmol) and
potassium tert-butoxide (3.64 g, 30.3 mmol) in THF (100 mL) was
stirred at room temperature for 30 minutes. The solution was cooled
at 0.degree. C. and [1,3,2]dioxathiane 2,2-dioxide (Example 291,
Step 5) (3.6 g, 26.34 mmol) in THF (25 mL) was added. The mixture
was stirred at room temperature for 5 hours, and the solvent was
removed under vacuum. The residue was dissolved in 6N HCl (15 mL)
and heated at 100.degree. C. for 16 hours. The mixture was cooled
to room temperature, and the aqueous phase was extracted with ethyl
acetate (3.times.30 mL). The combined organic layers were washed
with 11120 (3.times.25 mL) and brine (25 mL), dried (gSO.sub.4),
filtered, and concentrated to produce a white solid. .sup.1H-NMR
(200.15 MHz, CDCl.sub.3): d 7.57-7.49 (m, 4H), 7.45-7.37 (m, 3H),
6.98 (dd, 2H, J=6.72, 2.14), 4.17 (t, 2H, J=5.9), 3.88 (q, 2H,
J=5.9), 2.07 (qn, 2H, J=5.9).
[2237] Step 7: 4-(3-bromo-propoxy)-biphenyl 580
[2238] Triphenylphosphine (1.61 g, 6.14 mmol) was added to a
solution of 3-(biphenyl-4-yloxy)-propan-1-ol (Example 291, Step 6)
(1.00 g, 4.38 mmol) and carbon tetrabromide (1.81 g, 5.47 mmol) in
CH.sub.2Cl.sub.2 (20 mL) at 0.degree. C. The mixture was warmed to
room temperature and stirred for about an hour and then extracted
with ethyl acetate (50 mL). The organic layer was washed with
H.sub.2O (3.times.50 mL) and brine (3.times.25 mL), and then dried
(MgSO.sub.4), filtered and concentrated. The crude product was
purified by silica gel column chromatography (silica gel,
hexanes/ethyl acetate, 9:1) to produce
4-(3-bromo-propoxy)-biphenyl. .sup.1H-NMR (200.15 MHz, CDCl.sub.3):
d 7.57-7.29 (m, 7H), 6.98 (dd, 2H, J=6.72, 1.88), 4.45 (t, 2H,
J=5.92), 3.62 (t, 2H, J=6.44), 2.34 (qn, 2H, J=5.92).
[2239] Step 8:
3-{3-[3-(biphenyl-4-yloxy)-propoxy]-phenyl}-2-methoxy-propi- onic
acid (Isomer 1) 581
[2240] The title compound was prepared from
4-(3-bromo-propoxy)-biphenyl (Example 291, Step 7) and
3-(3-hydroxy-phenyl)-2-methoxy-propionic acid methyl ester (Example
291, Step 4) (0.3 g, 1.42 mmol) via the same procedure used for the
preparation of (2S)-3-{4-[2-(biphenyl-4-yloxy)-eth-
oxy]-phenyl}-2-methoxy-propionic acid (Example 283, Step 3). The
crude material was submitted to chiral HPLC separation to afford
the single enantiomer of isomer 1. .sup.1H-NMR (CDCl.sub.3, 200.15
MHz): 7.57-7.17 (m, 7H), 6.99 (dd, 2H, J=6.7, 2.2), 6.85-6.80 (m,
3H), 4.19 (dd, 4H, J=13.4, 6.4), 4.03 (dd, 1H, J=7.3, 4.3), 3.40
(s, 3H), 0.14 (dd, 1H, J=14.0, 4.3), 2.98 (dd, 1H, J=14.8, 7.5),
2.28 (qui, 2H, J=5.9).
EXAMPLE 292
[2241]
3-{3-[3-(biphenyl-4-yloxy)-propoxy]-phenyl}-2-methoxy-propionic
acid (Isomer 2) 582
[2242] The title compound was prepared from
4-(3-bromo-propoxy)-biphenyl (Example 291, Step 7), and
3-(3-hydroxy-phenyl)-2-methoxy-propionic acid methyl ester (Example
291, Step 4) via the same procedure used for the preparation of
(2S)-3-{4-[2-(biphenyl-4-yloxy)-ethoxy]-phenyl}-2-methoxy--
propionic acid (Example 283, Step 3). The crude material was
submitted to chiral HPLC separation to afford the single enantiomer
of isomer 2. .sup.1H-NMR (CDCl.sub.3, 200.15 MHz): 7.57-7.17 (m,
7H), 6.99 (dd, 2H, J=6.7, 2.2), 6.85-6.80 (m, 3H), 4.19 (dd, 4H,
J=13.4, 6.4), 4.03 (dd, 1H, J=7.3, 4.3), 3.40 (s, 3H), 0.14 (dd,
1H, J=14.0, 4.3), 2.98 (dd, 1H, J=14.8, 7.5), 2.28 (qn, 2H,
J=5.9).
EXAMPLE 293
[2243]
(2S)-3-{4-[3-(2-cyano-phenoxy)-propoxy]-phenyl}-2-methoxy-propionic
acid 583
[2244] The title compound was prepared from
(2S)-3-[4-(3-bromo-propoxy)-ph- enyl]-2-methoxy-propionic acid
ethyl ester (Example 284, Step 2) and 2-hydroxy benzonitrile via
the same procedure used for the preparation of
(2S)-2-methoxy-3-[4-(3-phenoxy-propoxy)-phenyl]-propionic acid
(Example 285, Step 1), to produce a colorless oil.
[2245] MS (ES) for C.sub.20H.sub.21NO.sub.5 [M+NH.sub.4].sup.+:
373.4.
EXAMPLE 294
[2246]
(2S)-2-methoxy-3-{4-[3-(2-methoxy-phenoxy)-propoxy]-phenyl}-propion-
ic acid 584
[2247] The title compound was prepared from
(2S)-3-[4-(3-bromo-propoxy)-ph- enyl]-2-methoxy-propionic acid
ethyl ester (Example 284, Step 2) and 2-methoxy-phenol via the same
procedure used for the preparation of
(2S)-2-methoxy-3-[4-(3-phenoxy-propoxy)-phenyl]-propionic acid
(Example 285, Step 1), to produce a colorless oil. MS (ES) for
C.sub.20H.sub.24O.sub.6 [M+NH.sub.4].sup.+: 378.4.
EXAMPLE 295
[2248]
(2S)-2-{3-[4-(2-carboxy-2-methoxy-ethyl)-phenoxy]-propoxy}-benzoic
acid 585
[2249] The title compound was prepared from
(2S)-3-[4-(3-bromo-propoxy)-ph- enyl]-2-methoxy-propionic acid
ethyl ester (Example 284, Step 2) and 2-hydroxy-benzoic acid methyl
ester via the same procedure used for the preparation of
(2S)-2-methoxy-3-[4-(3-phenoxy-propoxy)-phenyl]-propionic acid
(Example 285, Step 1), to produce a colorless oil.
[2250] MS (ES) for C.sub.20H.sub.22O.sub.7 [M+H].sup.+: 375.2.
EXAMPLE 296
[2251]
(2S)-3-{4-[3-(3-cyano-phenoxy)-propoxy]-phenyl}-2-methoxy-propionic
acid 586
[2252] The title compound was prepared from
(2S)-3-[4-(3-bromo-propoxy)-ph- enyl]-2-methoxy-propionic acid
ethyl ester (Example 284, Step 2) and 3-hydroxy-benzonitrile via
the same procedure used for the preparation of
(2S)-2-methoxy-3-[4-(3-phenoxy-propoxy)-phenyl]-propionic acid
(Example 285, Step 1), to produce a colorless oil.
[2253] MS (ES) for C.sub.20H.sub.21NO.sub.5 [M+NH.sub.4].sup.+:
373.4.
EXAMPLE 297
[2254] (2S)-3-{4-[3-(3
ethylamino-phenoxy)-propoxy]-phenyl}-2-methoxy-prop- ionic acid
587
[2255] The title compound was prepared from
(2S)-3-[4-(3-bromo-propoxy)-ph- enyl]-2-methoxy-propionic acid
ethyl ester (Example 284, Step 2) and 3-dimethylamino-phenol via
the same procedure used for the preparation of
(2S)-2-methoxy-3-[4-(3-phenoxy-propoxy)-phenyl]-propionic acid
(Example 285, Step 1), to produce a colorless oil.
[2256] MS (ES) for C.sub.2H.sub.27NO.sub.5 [M+H].sup.+: 374.4.
EXAMPLE 298
[2257]
(2S)-3-{3-[4-(2-carboxy-2-methoxy-ethyl)-phenoxy]-propoxy}-benzoic
acid 588
[2258] The title compound was prepared from
(2S)-3-[4-(3-bromo-propoxy)-ph- enyl]-2-methoxy-propionic acid
ethyl ester (Example 284, Step 2) and 3-hydroxy-benzoic acid methyl
ester via the same procedure used for the preparation of
(2S)-2-methoxy-3-[4-(3-phenoxy-propoxy)-phenyl]-propionic acid
(Example 285, Step 1), to produce a colorless oil.
[2259] MS (ES) for C.sub.20H.sub.22O.sub.7 [M+Na].sup.+: 397.4.
EXAMPLE 299
[2260]
(2S)-3-{4-[3-(indan-5-yloxy)-propoxy]-phenyl}-2-methoxy-propionic
acid 589
[2261] The title compound was prepared from
(2S)-3-[4-(3-bromo-propoxy)-ph- enyl]-2-methoxy-propionic acid
ethyl ester (Example 284, Step 2) and indan-5-ol via the same
procedure used for the preparation of
(2S)-2-methoxy-3-[4-(3-phenoxy-propoxy)-phenyl]-propionic acid
(Example 285, Step 1), to produce a colorless oil. MS (ES) for
C.sub.22H.sub.25O.sub.5 [M+Na].sup.+: 393.4.
EXAMPLE 300
[2262]
(2S)-2-methoxy-3-{4-[3-(naphthalen-2-yloxy)-propoxy]-phenyl}-propio-
nic acid 590
[2263] The title compound was prepared from
(2S)-3-[4-(3-bromo-propoxy)-ph- enyl]-2-methoxy-propionic acid
ethyl ester Example 284, Step 2) and naphthalen-2-ol via the same
procedure used for the preparation of
(2S)-2-methoxy-3-[4-(3-phenoxy-propoxy)-phenyl]-propionic acid
(Example 285, Step 1), to produce a colorless oil. MS (ES) for
C.sub.23H.sub.24O.sub.5 [M+Na].sup.+: 403.4.
EXAMPLE 301
[2264]
(2S)-3-{4-[3-(1H-indol-5-yloxy-propoxy]-phenyl}-2-methoxy-propionic
acid 591
[2265] The title compound was prepared from
(2S)-3-[4-(3-bromo-propoxy)-ph- enyl]-2-methoxy-propionic acid
ethyl ester (Example 284, Step 2) and 1H-indol-5-ol via the same
procedure used for the preparation of
(2S)-2-methoxy-3-[4-(3-phenoxy-propoxy)-phenyl]-propionic acid
(Example 285, Step 1), to produce a colorless oil. MS (ES) for
C.sub.2H.sub.2O.sub.5 [M+1.].sup.+: 370.4.
EXAMPLE 302
[2266]
(2S)-2-methoxy-3-{4-[3-(quinolin-6-yloxy)-propoxy]-phenyl}-propioni-
c acid 592
[2267] The title compound was prepared from
(2S)-3-[4-(3-bromo-propoxy)-ph- enyl]-2-methoxy-propionic acid
ethyl ester (Example 284, Step 2) and quinolin-6-ol via the same
procedure used for the preparation of
(2S)-2-methoxy-3-[4-(3-phenoxy-propoxy)-phenyl]-propionic acid
(Example 285, Step 1), to produce a colorless oil. MS (ES) for
C.sub.22H.sub.23NO.sub.5 [M+H].sup.+: 382.4.
EXAMPLE 303
[2268]
(2S)-2-methoxy-3-{4-[3-(3-methoxy-phenoxy)-propoxy]-phenyl}-propion-
ic acid 593
[2269] The title compound was prepared from
(2S)-3-[4-(3-bromo-propoxy)-ph- enyl]-2-methoxy-propionic acid
ethyl ester (Example 284, Step 2) and 3-methoxy-phenol via the same
procedure used for the preparation of
(2S)-2-methoxy-3-[4-(3-phenoxy-propoxy)-phenyl]-propionic acid
(Example 285, Step 1), to produce a colorless oil. MS (ES) for
C.sub.20H.sub.24O.sub.6 [M+H].sup.+: 361.4.
EXAMPLE 304
[2270]
(2S)-3-{4-[3-(3-fluoro-phenoxy)-propoxy]-phenyl}-2-methoxy-propioni-
c acid 594
[2271] The title compound was prepared from
(2S)-3-[4-(3-bromo-propoxy)-ph- enyl]-2-methoxy-propionic acid
ethyl ester (Example 284, Step 2) and 3-fluoro-phenol via the same
procedure used for the preparation of
(2S)-2-methoxy-3-[4-(3-phenoxy-propoxy)-phenyl]-propionic acid
(Example 285, Step 1), to produce a colorless oil. MS (ES) for
C.sub.19H.sub.21FO.sub.5 [M+Na].sup.+: 371.4.
EXAMPLE 305
[2272]
(2S)-3-{4-[3-(2-isopropyl-phenoxy)-propoxy]-phenyl}-2-methoxy-propi-
onic acid 595
[2273] The title compound was prepared from
(2S)-3-[4-(3-bromo-propoxy)-ph- enyl]-2-methoxy-propionic acid
ethyl ester (example 284, Step 2) and 2-isopropyl-phenol via the
same procedure used for the preparation of
(2S)-2-methoxy-3-[4-(3-phenoxy-propoxy)-phenyl]-propionic acid
(example 285, Step 1), to produce a colorless oil. MS (ES) for
C.sub.22H.sub.28O.sub.5 [M+NH.sub.4].sup.+: 390.4.
EXAMPLE 306
[2274] (2S)-2-methoxy-3-[4-(2-phenoxy-ethoxy)-phenyl]-propionic
acid 596
[2275] The title compound was prepared from
(2S)-3-[4-(2-bromo-ethoxy)-phe- nyl]-2-methoxy-propionic acid ethyl
ester Example 283, Step 2) and phenol via the same procedure used
for the preparation of
(2S)-2-methoxy-3-[4-(3-phenoxy-propoxy)-phenyl]-propionic acid
(Example 285, Step 1), to produce a white solid. MS (ES) for
C.sub.18H.sub.20O.sub.5 [M+Na].sup.+: 339.3.
EXAMPLE 307
[2276]
(2S)-3-{4-[2-(2-cyano-phenoxy)-ethoxy]-phenyl}-2-methoxy-propionic
acid 597
[2277] The title compound was prepared from
(2S)-3-[4-(2-bromo-ethoxy)-phe- nyl]-2-methoxy-propionic acid ethyl
ester (Example 283, Step 2) and 2-hydroxy-benzonitrile via the same
procedure used for the preparation of
(2S)-2-methoxy-3-[4-(3-phenoxy-propoxy)-phenyl]-propionic acid
(Example 285, Step 1), to produce a colorless oil.
[2278] MS (ES) for C.sub.19H.sub.11NO.sub.5 [M-H].sup.-: 340.3.
EXAMPLE 308
[2279]
(2S)-2-methoxy-3-{4-[2-(2-methoxy-phenoxy)-ethoxy]-phenyl}-propioni-
c acid 598
[2280] The title compound was prepared from
(2S)-3-[4-(2-bromo-ethoxy)-phe- nyl]-2-methoxy-propionic acid ethyl
ester (Example 283, Step 2) and 2-methoxy-phenol via the same
procedure used for the preparation of
(2S)-2-methoxy-3-[4-(3-phenoxy-propoxy)-phenyl]-propionic acid
(Example 285, Step 1), to produce a white solid. MS (ES) for
C.sub.19H.sub.22O.sub.6 [M+Na].sup.+: 369.4.
EXAMPLE 309
[2281]
(2S)-3-{4-[2-(biphenyl-2-yloxy)-ethoxy]-phenyl}-2-methoxy-propionic
acid 599
[2282] The title compound was prepared from
(2S)-3-[4-(2-bromo-ethoxy)-phe- nyl]-2-methoxy-propionic acid ethyl
ester (Example 283, Step 2) and biphenyl-2-ol via the same
procedure used for the preparation of
(2S)-2-methoxy-3-[4-(3-phenoxy-propoxy)-phenyl]-propionic acid
(Example 285, Step 1), to produce a colorless oil. MS (ES) for
C.sub.24H.sub.24O.sub.5 [M+Na].sup.+: 415.4.
EXAMPLE 310
[2283]
(2S)-2-{2-[4-(2-carboxy-2-methoxy-ethyl)-phenoxy]-ethoxy}-benzoic
acid 600
[2284] The title compound was prepared from
(2S)-3-[4-(2-bromo-ethoxy)-phe- nyl]-2-methoxy-propionic acid ethyl
ester (Example 283, Step 2) and 2-hydroxy-benzoic acid methyl ester
via the same procedure used for the preparation of
(2S)-2-methoxy-3-[4-(3-phenoxy-propoxy)-phenyl]-propionic acid
(Example 285, Step 1), to produce a colorless oil. MS (ES) for
C.sub.19H.sub.20O.sub.7 [M+Na].sup.+: 383.3.
EXAMPLE 311
[2285]
(2S)-3-{4-[2-(2-isopropyl-phenoxy)-ethoxy]-phenyl}-2-methoxy-propio-
nic acid 601
[2286] The title compound was prepared from
(2S)-3-[4-(2-bromo-ethoxy)-phe- nyl]-2-methoxy-propionic acid ethyl
ester (Example 283, Step 2) and 2-isopropyl-phenol via the same
procedure used for the preparation of
(2S)-2-methoxy-3-[4-(3-phenoxy-propoxy)-phenyl]-propionic acid
(Example 285, Step 1), to produce a white solid. MS (ES) for
C.sub.2H.sub.26O.sub.5 [M+Na].sup.+: 381.4.
EXAMPLE 312
[2287]
(2S)-3-{4-[2-(3-cyano-phenoxy)-ethoxy]-phenyl}-2-methoxy-propionic
acid 602
[2288] The title compound was prepared from
(2S)-3-[4-(2-bromo-ethoxy)-phe- nyl]-2-methoxy-propionic acid ethyl
ester (Example 283, Step 2) and 3-hydroxy-benzonitrile via the same
procedure used for the preparation of
(2S)-2-methoxy-3-[4-(3-phenoxy-propoxy)-phenyl]-propionic acid
(Example 285, Step 1), to produce a white solid.
[2289] MS (ES) for C.sub.19H.sub.19NO.sub.5 [M-H].sup.-: 340.3.
EXAMPLE 313
[2290]
(2S)-3-{4-[2-(3-dimethylamino-phenoxy)-ethoxy]-phenyl}-2-methoxy-pr-
opionic acid 603
[2291] The title compound was prepared from
(2S)-3-[4-(2-bromo-ethoxy)-phe- nyl]-2-methoxy-propionic acid ethyl
ester (Example 283, Step 2) and 3-dimethylamino-phenol via the same
procedure used for the preparation of
(2S)-2-methoxy-3-[4-(3-phenoxy-propoxy)-phenyl]-propionic acid
(Example 285, Step 1), to produce a yellow oil.
[2292] MS (ES) for C.sub.2H.sub.26O.sub.5 [M+H].sup.+: 360.4.
EXAMPLE 314
[2293]
(2S)-3-{4-[2-(biphenyl-3-yloxy)-ethoxy]-phenyl}-2-methoxy-propionic
acid 604
[2294] The title compound was prepared from
(2S)-3-[4-(2-bromo-ethoxy)-phe- nyl]-2-methoxy-propionic acid ethyl
ester (example 283, Step 2) and biphenyl-3-ol via the same
procedure used for the preparation of
(2S)-2-methoxy-3-[4-(3-phenoxy-propoxy)-phenyl]-propionic acid.
(Example 285, Step 1), to produce a white solid. MS (ES) for
C.sub.24H.sub.24O.sub.5 [M-H].sup.-: 391.4.
EXAMPLE 315
[2295]
(2S)-3-{2-[4-(2-carboxy-2-methoxy-ethyl)-phenoxy]-ethoxy}-benzoic
acid 605
[2296] The title compound was prepared from
(2S)-3-[4-(2-bromo-ethoxy)-phe- nyl]-2-methoxy-propionic acid ethyl
ester (Example 283, Step 2) and 3-hydroxybenzoic acid methyl ester
via the same procedure used for the preparation of
(2S)-2-methoxy-3-[4-(3-phenoxy-propoxy)-phenyl]-propionic acid
(Example 285, Step 1), to produce a white solid.
[2297] MS (ES) for C.sub.19H.sub.20O.sub.7 [M-H].sup.-: 359.3.
EXAMPLE 316
[2298]
(2S)-3-{4-[2-(indan-5-yloxy)-ethoxy]-phenyl}-2-methoxy-propionic
acid 606
[2299] The title compound was prepared from
(2S)-3-[4-(2-bromo-ethoxy)-phe- nyl]-2-methoxy-propionic acid ethyl
ester (Example 283, Step 2) and indan-5-ol via the same procedure
used for the preparation of
(2S)-2-methoxy-3-[4-(3-phenoxy-propoxy)-phenyl]-propionic acid
(Example 285, Step 1), to produce a colorless oil. MS (ES) for
C.sub.2H.sub.24O.sub.5 [M-H].sup.-: 355.3.
EXAMPLE 317
[2300]
(2S)-2-methoxy-3-{4-[2-(naphthalen-2-yloxy)-ethoxy]-phenyl}-propion-
ic acid 607
[2301] The title compound was prepared from
(2S)-3-[4-(2-bromo-ethoxy)-phe- nyl]-2-methoxy-propionic acid ethyl
ester (Example 283, Step 2) and naphthalen-2-ol via the same
procedure used for the preparation of
(2S)-2-methoxy-3-[4-(3-phenoxy-propoxy)-phenyl]-propionic acid
(Example 285, Step 1), to produce a white solid. MS (ES) for
C.sub.22H.sub.22O.sub.5 [M+NH.sub.4].sup.+: 389.3.
EXAMPLE 318
[2302]
(2S)-2-Methoxy-3-{4-[2-(quinolin-6-yloxy)-ethoxy]-phenyl}-propionic
acid 608
[2303] The title compound was prepared from
(2S)-3-[4-(2-bromo-ethoxy)-phe- nyl]-2-methoxy-propionic acid ethyl
ester (Example 283, Step 2) and quinolin-6-ol via the same
procedure used for the preparation of
(2S)-2-methoxy-3-[4-(3-phenoxy-propoxy)-phenyl]-propionic acid
(Example 285, Step 1), to produce a white solid. MS (ES) for
C.sub.2H.sub.21NO.sub.5 [M+H].sup.+: 368.3.
EXAMPLE 319
[2304]
(2S)-2-Methoxy-3-{4-[2-(3-morpholin-4-yl-phenoxy)-ethoxy]-phenyl}-p-
ropionic acid 609
[2305] The title compound was prepared from
(2S)-3-[4-(2-bromo-ethoxy)-phe- nyl]-2-methoxy-propionic acid ethyl
ester (Example 283, Step 2) and 3-morpholin-4-yl-phenol via the
same procedure used for the preparation of
(2S)-2-methoxy-3-[4-(3-phenoxy-propoxy)-phenyl]-propionic acid
(Example 285, Step 1), to produce a yellow oil.
[2306] MS (ES) for C.sub.22H.sub.27NO.sub.6 [M+H]+402.4.
EXAMPLE 320
[2307]
(2S)-2-methoxy-3-{4-[2-(2-methyl-benzothiazol-5-yloxy)-ethoxy]-phen-
yl}-propionic acid 610
[2308] The title compound was prepared from
(2S)-3-[4-(2-bromo-ethoxy)-phe- nyl]-2-methoxy-propionic acid ethyl
ester (Example 283, Step 2) and 2-methyl-benzothiazol-5-ol via the
same procedure used for the preparation of
(2S)-2-methoxy-3-[4-(3-phenoxy-propoxy)-phenyl]-propionic acid
(Example 285, Step 1), to produce a yellow oil.
[2309] MS (ES) for C.sub.20H.sub.21NO.sub.5S [M+H].sup.+:
388.3.
EXAMPLE 321
[2310]
(2S)-2-methoxy-3-{4-[2-(3-methoxy-phenyl)-ethoxy]-phenyl}-propionic
acid 611
[2311] The title compound was prepared from
(2S)-3-[4-(2-bromo-ethoxy)-phe- nyl]-2-methoxy-propionic acid ethyl
ester (Example 283, Step 2) and 3-methoxy-phenol via the same
procedure used for the preparation of
(2S)-2-methoxy-3-[4-(3-phenoxy-propoxy)-phenyl]-propionic acid
(Example 285, Step 1), to produce a white solid. MS (ES) for
C.sub.19H.sub.22O.sub.6 [M-H].sup.-: 345.3.
EXAMPLE 322
[2312]
(2S)-3-{4-[2-(3-fluoro-phenoxy)-ethoxy]-phenyl}-2-methoxy-propionic
acid 612
[2313] The title compound was prepared from
(2S)-3-[4-(2-bromo-ethoxy)-phe- nyl]2-methoxy-propionic acid ethyl
ester (Example 283, Step 2) and 3-fluoro-phenol via the same
procedure used for the preparation of
(2S)-2-methoxy-3-[4-(3-phenoxy-propoxy)-phenyl]-propionic acid
(Example 285, Step 1), to produce a white solid. MS (ES) for
C.sub.18H.sub.19FO.sub.5 [M-H].sup.-: 333.3.
EXAMPLE 323
[2314] 2-methoxy-3-[3-(3-phenoxy-propoxy)-phenyl]-propionic acid
(isomer 1) 613
[2315] Step 1: 3-[3-(3-bromo-propoxy)-phenyl]-2-methoxy-propionic
acid methyl ester 614
[2316] The title compound was prepared from 3-bromo-propan-1-ol
(Example 284, Step 1) and 3-(3-hydroxy-phenyl)-2-methoxy-propionic
acid methyl ester (Example 291, Step 4) via the same procedure used
for the preparation of
(2S)-3-[4-(3-bromo-propoxy)-phenyl]-2-methoxy-propionic acid ethyl
ester (Example 284, Step 2). .sup.1H-NMR (CDCl.sub.3, 200.15 MHz):
7.26-7.16 (m, 1H), 6.80 (t, 3H, J=7.3), 4.09 (t, 2H, J=5.9), 3.97
(dd, 1H, J=7.3, 5.4), 3.73 (s, 3H), 3.60 (t, 2H, J=6.4), 3.36 (s,
3H), 3.00 (s, 1H), 2.97 (d, 1H, J=3.2), 2.31 (qn, 2H, J=6.2).
[2317] Step 2: (Isomer-1)
2-methoxy-3-[3-(3-phenoxy-propoxy)-phenyl]-propi- onic acid 615
[2318] The title compound was prepared from
3-[3-(3-bromo-propoxy)-phenyl]- -2-methoxy-propionic acid methyl
ester (Example 323, Step 1) and phenol via the same procedure used
for the preparation of
(2S)-2-methoxy-3-[4-(3-phenoxy-propoxy)-phenyl]-propionic acid
(Example 285, Step 1). The enatiomers were separated by chiral
HPLC. MS (ES) for C.sub.19H.sub.22O.sub.5 [M+Na].sup.+: 353.3.
EXAMPLE 324
[2319]
3-{3-[3-(2-cyano-phenoxy)-propoxy]-phenyl}-2-methoxy-propionic acid
(isomer 1) 616
[2320] The title compound was prepared from
3-[3-(3-bromo-propoxy)-phenyl]- -2-methoxy-propionic acid methyl
ester (Example 323, Step 1) and 2-cianophenol via the same
procedure used for the preparation of
(2S)-2-methoxy-3-[4-(3-phenoxy-propoxy)-phenyl]-propionic acid
(Example 285, Step 1). The enatiomers were separated by chiral
HPLC. MS (ES) for C.sub.20H.sub.21NO.sub.5 [M+Na].sup.+: 378.3.
EXAMPLE 325
[2321]
3-{3-[3-(3-cyano-phenoxy)-propoxy-phenyl]-2-methoxy-propionic acid
(isomer 1) 617
[2322] The title compound was prepared from
3-[3-(3-bromo-propoxy)-phenyl]- -2-methoxy-propionic acid methyl
ester Example 323, Step 1) and 3-cianophenol via the same procedure
used for the preparation of
(2S)-2-methoxy-3-[4-(3-phenoxy-propoxy)-phenyl]-propionic acid
(Example 285, Step 1). The enatiomers were separated by chiral
HPLC. MS (ES) for C.sub.20H.sub.2)NO.sub.5 [M+Na].sup.+: 378.3.
EXAMPLE 326
[2323] 2-methoxy-3-[3-(3-phenoxy-propoxy)-phenyl]-propionic acid
(isomer 2) 618
[2324] The title compound was prepared from
3-[3-(3-bromo-propoxy)-phenyl]- -2-methoxy-propionic acid methyl
ester (Example 323, Step 1) and phenol via the same procedure used
for the preparation of
(2S)-2-methoxy-3-[4-(3-phenoxy-propoxy)-phenyl]-propionic acid
(Example 285, Step 1). The enantiomers were separated by chiral
HPLC.
[2325] MS (ES) for C.sub.19H.sub.22O.sub.5 [M+Na].sup.+: 353.3.
EXAMPLE 327
[2326]
3-{3-[3-(2-cyano-phenyl)-propoxy]-phenyl}-2-methoxy-propionic acid
(isomer 2) 619
[2327] The title compound was prepared from
3-[3-(3-bromo-propoxy)-phenyl]- -2-methoxy-propionic acid methyl
ester (Example 323, Step 1) and 2-cianophenol via the same
procedure used for the preparation of
(2S)-2-methoxy-3-[4-(3-phenoxy-propoxy)-phenyl]-propionic acid
(Example 285, Step 1). The enatiomers were separated by chiral
HPLC. MS (ES) for C.sub.20H.sub.21NO.sub.5 [M+Na].sup.+: 378.3
EXAMPLE 328
[2328]
3-{3-[3-(3-cyano-phenoxy)-propoxy]-phenyl}-2-methoxy-propionic acid
(isomer 2) 620
[2329] The title compound was prepared from
3-[3-(3-bromo-propoxy)-phenyl]- -2-methoxy-propionic acid methyl
ester (Example 323, Step 1) and 3-cianophenol via the same
procedure used for the preparation of
(2S)-2-methoxy-3-[4-(3-phenoxy-propoxy)-phenyl]-propionic acid
(Example 285, Step 1). The enatiomers were separated by chiral
HPLC. MS (ES) for C.sub.20H.sub.21NO.sub.5 [M+Na].sup.+: 378.3
EXAMPLE 329
[2330]
2-methoxy-3-{3-[3-(2-methoxy-phenoxy)-propoxy]-phenyl}-propionic
acid (isomer 1) 621
[2331] The title compound was prepared from
3-[3-(3-bromo-propoxy)-phenyl]- -2-methoxy-propionic acid methyl
ester (Example 323, Step 1) and 2-methoxyphenol via the same
procedure used for the preparation of
(2S)-2-methoxy-3-[4-(3-phenoxy-propoxy)-phenyl]-propionic acid
(Example 285, Step 1). The enatiomers were separated by chiral
HPLC. MS (ES) for C.sub.20H.sub.24O.sub.6 [M+Na].sup.+: 383.4.
EXAMPLE 330
[2332]
2-methoxy-3-{3-[3-(2-methoxy-phenoxy)-propoxy]-phenyl}-propionic
acid (isomer 2) 622
[2333] The title compound was prepared from
3-[3-(3-bromo-propoxy)-phenyl]- -2-methoxy-propionic acid methyl
ester (Example 323, Step 1) and 2-methoxyphenol via the same
procedure used for the preparation of
(2S)-2-methoxy-3-[4-(3-phenoxy-propoxy)-phenyl]-propionic acid
(Example 285, Step 1). The enatiomers were separated by chiral
HPLC. MS (ES) for C.sub.20H.sub.24O.sub.6 [M+Na].sup.+: 383.4.
EXAMPLE 331
[2334]
3-{3-[3-(2-isopropyl-phenoxy)-propoxy]-phenyl}-2-methoxy-propionic
acid (isomer 623
[2335] The title compound was prepared from
3-[3-(3-bromo-propoxy)-phenyl]- -2-methoxy-propionic acid methyl
ester (Example 323, Step 1) and 2-isopropylphenol via the same
procedure used for the preparation of
(2S)-2-methoxy-3-[4-(3-phenoxy-propoxy)-phenyl]-propionic acid
(Example 285, Step 1). The enatiomers were separated by chiral
HPLC. MS (ES) for C.sub.22H.sub.28O.sub.5 [M+Na].sup.+: 395.4.
EXAMPLE 332
[2336]
3-{3-[3-(2-isopropyl-phenoxy)-propoxy]-phenyl}-2-methoxy-propionic
acid (isomer 2) 624
[2337] The title compound-was prepared from
3-[3-(3-bromo-propoxy)-phenyl]- -2-methoxy-propionic acid methyl
ester (Example 323, Step 1) and 2-isopropylphenol via the same
procedure used for the preparation of
(2S)-2-methoxy-3-[4-(3-phenoxy-propoxy)-phenyl]-propionic acid
(Example 285, Step 1). The enatiomers were separated by chiral
HPLC. MS (ES) for C.sub.22H.sub.28O.sub.5 [M+Na].sup.+: 395.4.
EXAMPLE 333
[2338] 3-{3-[3-2-carboxy-2-methoxy-ethyl)-phenoxy]-propoxy}-benzoic
acid (isomer 1) 625
[2339] The title compound was prepared from
3-[3-(3-bromo-propoxy)-phenyl]- -2-methoxy-propionic acid methyl
ester (Example 323, Step 1) and 3-hydroxybenzoic acid methyl ester
via the same procedure used for the preparation of
(2S)-2-methoxy-3-[4-(3-phenoxy-propoxy)-phenyl]-propionic acid
(Example 285, Step 1). The enatiomers were separated by chiral
HPLC. MS (ES) for C.sub.20H.sub.22O.sub.7 [M+Na].sup.+: 397.4.
EXAMPLE 334
[2340]
3-{3-[3-(2-carboxy-2-methoxy-ethyl)-phenoxy]-propoxy}-benzoic acid
(isomer 2) 626
[2341] The title compound was prepared from
3-[3-(3-bromo-propoxy)-phenyl]- -2-methoxy-propionic acid methyl
ester (Example 323, Step 1) and 3-hydroxybenzoic acid methyl ester
via the same procedure used for the preparation of
(2S)-2-methoxy-3-[4-(3-phenoxy-propoxy)-phenyl]-propionic acid
(Example 285, Step 1). The enatiomers were separated by chiral
HPLC. MS (ES) for C.sub.20H.sub.22O.sub.7 [M+Na].sup.+: 397.4.
EXAMPLE 335
[2342]
2-methoxy-3-{3-[3-(3-methoxy-phenoxy)-propoxy]-phenyl}-propionic
acid (isomer 1) 627
[2343] The title compound was prepared from
3-[3-(3-bromo-propoxy)-phenyl]- -2-methoxy-propionic acid methyl
ester (example 323, Step 1) and 3-methoxyphenol via the same
procedure used for the preparation of
(2S)-2-methoxy-3-[4-(3-phenoxy-propoxy)-phenyl]-propionic acid
(Example 285, Step 1). The enatiomers were separated by chiral
HPLC. MS (ES) for C.sub.20H.sub.24O.sub.6 [M+Na].sup.+: 383.3.
EXAMPLE 336
[2344]
2-methoxy-3-{3-[3-(3-methoxy-phenoxy)-propoxy]-phenyl}-propionic
acid (isomer 2) 628
[2345] The title compound was prepared from
3-[3-(3-bromo-propoxy)-phenyl]- -2-methoxy-propionic acid methyl
ester (Example 323, Step 1) and 3-methoxyphenol via the same
procedure used for the preparation of
(2S)-2-methoxy-3-[4-(3-phenoxy propoxy)-phenyl]-propionic acid
(Example 285, Step 1). The enatiomers were separated by chiral
HPLC. MS (ES) for C.sub.20H.sub.24O.sub.6 [M+Na].sup.+: 383.3.
EXAMPLE 337
[2346]
2-methoxy-3-{3-[3-(naphthalen-2-yloxy)-propoxy]-phenyl}-propionic
acid (isomer 1) 629
[2347] The title compound was prepared from
3-[3-(3-bromo-propoxy)-phenyl]- -2-methoxy-propionic acid methyl
ester (Example 323, Step 1) and 2-naphthol via the same procedure
used for the preparation of
(2S)-2-methoxy-3-[4-(3-phenoxy-propoxy)-phenyl]-propionic acid
(Example 285, Step 1). The enatiomers were separated by chiral
HPLC.
[2348] .sup.1H-NMR (CDCl.sub.3, 200.15 MHz): 7.78-7.69 (m, 3H),
7.47-7.12 (m, 5H), 6.84-6.81 (m, 3H), 4.28 (t, 2H, J=5.9), 4.19 (t,
2H, J=5.9), 4.02 (dd, 1H, J=7.5, 4.0), 3.38 (s, 3H), 3.13 (dd, 1H,
J=14.2, 4.3), 2.97 (dd, 1H, J=14.2, 7.5), 2.33 (qn, 2H, J=6.2). MS
(ES) for C.sub.23H.sub.24O.sub.5 [M+H].sup.+: 381.2.
EXAMPLE 338
[2349]
2-methoxy-3-{3-[3-naphthalen-2-yloxy)-propoxy]-phenyl}-propionic
acid (isomer 2) 630
[2350] The title compound was prepared from
3-[3-(3-bromo-propoxy)-phenyl]- -2-methoxy-propionic acid methyl
ester (Example 323, Step 1) and 2-naphthol via the same procedure
used for the preparation, of
(2S)-2-methoxy-3-[4-(3-phenoxy-propoxy)-phenyl]-propionic acid
(Example 285, Step 1). The enatiomers were separated by chiral
HPLC.
[2351] .sup.1H-NMR (CDCl.sub.3, 200.15 MHz): 7.78-7.69 (m, 3H),
7.47-7.12 (m, 5H), 6.84-6.81 (m, 3H), 4.28 (t, 2H, J=5.9), 4.19 (t,
2H, J=5.9), 4.02 (dd, 1H, J=7.5, 4.0), 3.38 (s, 3H), 3.13 (dd, 1H,
J=14.2, 4.3), 2.97 (dd, 1H, J=14.2, 7.5), 2.33 (qn, 2H, J=6.2). MS
(ES) for C.sub.23H.sub.24O.sub.5 [M+H].sup.+: 381.2.
EXAMPLE 339
[2352]
2-methoxy-3-{3-[3-(2-methyl-benzothiazol-5-yloxy)-propoxy]-phenyl}--
propionic acid (isomer 1) 631
[2353] The title compound was prepared from
3-[3-(3-bromo-propoxy)-phenyl]- -2-methoxy-propionic acid methyl
ester (Example 323, Step 1) and 2-methyl-benzothiazol-5-ol via the
same procedure used for the preparation of
(2S)-2-methoxy-3-[4-(3-phenoxy-propoxy)-phenyl]-propionic acid
(Example 285, Step 1). The enatiomers were separated by chiral
HPLC. MS (ES) for C.sub.2H.sub.23NO.sub.5S [M+H].sup.+: 402.1.
EXAMPLE 340
[2354]
2-methoxy-3-3-[3-(2-methyl-benzothiazol-5-yloxy)-propoxy]-phenyl}-p-
ropionic acid (isomer 2) 632
[2355] The title compound was prepared from
3-[3-(3-bromo-propoxy)-phenyl]- -2-methoxy-propionic acid methyl
ester (Example 323, Step 1) and 2-methyl-benzothiazol-5-ol via the
same procedure used for the preparation of
(2S)-2-methoxy-3-[4-(3-phenoxy-propoxy)-phenyl]-propionic acid
(Example 285, Step 1). The enatiomers were separated by chiral
HPLC. MS (ES) for C.sub.2H.sub.23NO.sub.5S [M+H].sup.+: 402.1.
EXAMPLE 341
[2356]
3-{3-[3-(2-chloro-phenoxy)-propoxy]-phenyl}-2-methoxy-propionic
acid (isomer 1) 633
[2357] The title compound was prepared from
3-[3-(3-bromo-propoxy)-phenyl]- -2-methoxy-propionic acid methyl
ester (Example 323, Step 1) and 2-chlorophenol via the same
procedure used for the preparation of
(2S)-2-methoxy-3-[4-(3-phenoxy-propoxy)-phenyl]-propionic acid
(Example 285, Step 1). The enatiomers were separated by chiral
HPLC. .sup.1H-NMR (CDCl.sub.3, 200.15 MHz): 7.35 (dd, 1H, J=8.1,
1.9), 7.24-7.16 (m, 2H), 6.97-6.80 (m, 5H), 4.22 (t, 2H, J=5.9),
4.20 (t, 2H, J=5.9), 4.02 (dd, 1H, J=7.3, 4.0), 3.39 (s, 3H), 3.13
(dd, 1H, J=14.2, 3.8), 2.97 (dd, 1H, J=14.0, 7.8), 2.30 (qn, 2H,
J=6.2).
[2358] MS (ES) for C.sub.19H.sub.21ClO.sub.5 [M+Na].sup.+:
387.2.
EXAMPLE 342
[2359]
3-{3-[3-(2-chloro-phenoxy)-propoxy]-phenyl}-2-methoxy-propionic
acid (isomer 2) 634
[2360] The title compound was prepared from
3-[3-(3-bromo-propoxy)-phenyl]- -2-methoxy-propionic acid methyl
ester (Example 323, Step 1) and 2-chlorophenol via the same
procedure used for the preparation of
(2S)-2-methoxy-3-[4-(3-phenoxy-propoxy)-phenyl]-propionic acid
(Example 285, Step 1). The enatiomers were separated by chiral
HPLC. .sup.1H-NMR (CDCl.sub.3, 200.15 MHz): 7.35 (dd, 1H, J=8.1,
1.9), 7.24-7.16 (m, 2H), 6.97-6.80 (m, 5H), 4.22 (t, 2H, J=5.9),
4.20 (t, 2H, J=5.9), 4.02 (dd, 1H, J=7.3, 4.0), 3.39 (s, 3H), 3.13
(dd, 1H, J=14.2, 3.8), 2.97 (dd, 1H, J=14.0, 7.8), 2.30 (qn, 2H,
J=6.2).
[2361] MS (ES) for C.sub.19H.sub.21ClO.sub.5 [M+Na].sup.+:
387.2.
EXAMPLE 343
[2362]
3-{3-[3-(3,4-dimethyl-phenoxy)-propoxy]-phenyl}-2-methoxy-propionic
acid (isomer 1) 635
[2363] The title compound was prepared from
3-[3-(3-bromo-propoxy)-phenyl]- -2-methoxy-propionic acid methyl
ester (Example 323, Step 1) and 3,4-dimethylphenol via the same
procedure used for the preparation of
(2S)-2-methoxy-3-[4-(3-phenoxy-propoxy)-phenyl]-propionic acid
(Example 285, Step 1). The enatiomers were separated by chiral
HPLC. .sup.1H-NMR (CDCl.sub.3, 200.15 MHz): 7.18 (d, 1H, J=7.5),
7.02 (d, 1H, J=8.3), 6.84-6.62 (m, 5H), 4.14 (t, 2H, J=6.4), 4.12
(t, 2H, J=5.9), 4.02 (dd, 1H, J=7.3, 4.0), 3.39 (s, 3H), 3.13 (dd,
1H, J=14.2, 4.6), 2.97 (dd, 1H, J=14.0, 7.5), 2.23 (q, 1H,
J=6.2.1), 2.22 (s, 3H), 2.18 (s, 3H). MS (ES) for
C.sub.2H.sub.26O.sub.5 [M+Na].sup.+: 381.2.
EXAMPLE 344
[2364]
3-{3-[3-(3,4-dimethyl-phenoxy)-propoxy]-phenyl}-2-methoxy-propionic
acid (isomer 2) 636
[2365] The title compound was prepared from
3-[3-(3-bromo-propoxy)-phenyl]- -2-methoxy-propionic acid methyl
ester (Example 323, Step 1) and 3,4-dimethylphenol via the same
procedure used for the preparation of
(2S)-2-methoxy-3-[4-(3-phenoxy-propoxy)-phenyl]-propionic acid
(Example 285, Step 1). The enatiomers were separated by chiral
HPLC. .sup.1H-NMR (CDCl.sub.3, 200.15 MHz): 7.18 (d, 1H, J=7.5),
7.02 (d, 1H, J=8.3), 6.84-6.62 (m, 5H), 4.14 (t, 2H, J=6.4), 4.12
(t, 2H, J=5.9), 4.02 (dd, 1H, J=7.3, 4.0), 3.39 (s, 3H), 3.13 (dd,
1H, J=14.2, 4.6), 2.97 (dd, 1H, J=14.0, 7.5), 2.23 (q, 1H,
J=6.2.1), 2.22 (s, 3H), 2.18 (s, 3H). MS (ES) for
C.sub.21H.sub.26O.sub.5 [M+Na].sup.+: 381.2.
EXAMPLE 345
[2366]
2-{3-[3-(2-carboxy-2-methoxy-ethyl)-phenoxy]-propoxy}-benzoic acid
(isomer 1) 637
[2367] The title compound was prepared from
3-[3-(3-bromo-propoxy)-phenyl]- -2-methoxy-propionic acid methyl
ester (Example 323, Step. 1) and 2-hydroxy-benzoic acid via the
same procedure used for the preparation of
(2S)-2-methoxy-3-[4-(3-phenoxy-propoxy)-phenyl]-propionic acid
(example 285, Step 1). The enatiomers were separated by chiral
HPLC. MS (ES) for C.sub.20H.sub.17 [M+H].sup.+: 375.2.
EXAMPLE 346
[2368]
2-{3-[3-(2-carboxy-2-methoxy-ethyl)-phenoxy]-propoxy}-benzoic acid
(isomer 2) 638
[2369] The title compound was prepared from
3-[3-(3-bromo-propoxy)-phenyl]- -2-methoxy-propionic acid methyl
ester (Example 323, Step 1) and 2-hydroxy-benzoic acid via the same
procedure used for the preparation of
(2S)-2-methoxy-3-[4-(3-phenoxy-propoxy)-phenyl]-propionic acid
(Example 285, Step 1). The enatiomers were separated by chiral
HPLC. MS (ES) for C.sub.20H.sub.22O.sub.7 [M+H].sup.+: 375.2.
EXAMPLE 347
[2370]
3-{3-[3-(biphenyl-3-yloxy)-propoxy]-phenyl}-2-methoxy-propionic
acid (isomer 1) 639
[2371] The title compound was prepared from
3-[3-(3-bromo-propoxy)-phenyl]- -2-methoxy-propionic acid methyl
ester (Example 323, Step 1) and biphenyl-3-ol via the same
procedure used for the preparation of
(2S)-2-methoxy-3-[4-(3-phenoxy-propoxy)-phenyl]-propionic acid
(Example 285, Step 1). The enatiomers were separated by chiral
HPLC. MS (ES) for C.sub.25H.sub.26O.sub.5 [M+Na].sup.+: 429.2.
EXAMPLE 348
[2372]
3-{3-[3-(biphenyl-3-yloxy)-propoxy]-phenyl}-2-methoxy-propionic
acid (isomer 2) 640
[2373] The title compound was prepared from
3-[3-(3-bromo-propoxy)-phenyl]- -2-methoxy-propionic acid methyl
ester (Example 323, Step 1) and biphenyl-3-ol via the same
procedure used for the preparation of
(2S)-2-methoxy-3-[4-(3-phenoxy-propoxy)-phenyl]-propionic acid
(Example 285, Step 1). The enatiomers were separated by chiral
HPLC. MS (ES) for C.sub.25H.sub.26O.sub.5 [M+Na].sup.+: 429.2.
EXAMPLE 349
[2374]
2-methoxy-3-{3-[3-(quinolin-6-yloxy)-propoxy]-phenyl}-propionic
acid (isomer 1) 641
[2375] The title compound was prepared from
3-[3-(3-bromo-propoxy)-phenyl]- -2-methoxy-propionic acid methyl
ester (Example 323, Step 1) and quinolin-6-ol via the same
procedure used for the preparation of
(2S)-2-methoxy-3-[4-(3-phenoxy-propoxy)-phenyl]-propionic acid
(Example 285, Step 1). The enatiomers were separated by chiral
HPLC. MS (ES) for C.sub.22H.sub.23NO.sub.5 [M+H].sup.+: 382.2.
EXAMPLE 350
[2376]
2-methoxy-3-{3-[3-(quinolin-6-yloxy)-propoxy]-phenyl}-propionic
acid (isomer 2) 642
[2377] The title compound was prepared from
3-[3-(3-bromo-propoxy)-phenyl]- -2-methoxy-propionic acid methyl
ester Example 323, Step 1) and quinolin-6-ol via the same procedure
used for the preparation of (2S)-2-methoxy-3-[4-(3-phenoxy-propoxy)
phenyl]-propionic acid (Example 285, Step 1). The enatiomers were
separated by chiral HPLC. MS (ES) for C.sub.22H.sub.23NO.sub.5
[M+H].sup.+: 382.2.
EXAMPLE 351
[2378]
3-{3-[2-(2-isopropyl-phenoxy)-ethoxy-phenyl-2-ethoxy]-phenyl}-2-met-
hoxy-propionic acid (isomer 2) 643
[2379] Step 1: 3-[3-(2-bromo-ethoxy)-phenyl]-2-methoxy-propionic
acid methyl ester 644
[2380] The title compound was prepared from
3-(3-hydroxy-phenyl)-2-methoxy- -propionic acid methyl ester
(Example 291, Step 4) (4.76 mol, 1000 mg) via the same procedure
used for the preparation of (2S)-3-[4-(2-bromo-ethoxy)-
-phenyl]-2-methoxy-propionic acid ethyl ester (Example 283, Step
2). MS (ES) for C.sub.13H.sub.17BrO.sub.4 [M+NH.sub.4].sup.+:
334:2.
[2381] Step 2:
3-{3-[2-(2-isopropyl-phenoxy)-ethoxy]-phenyl}-2-methoxy-pro- pionic
acid (isomer 2) 645
[2382] The title compound was prepared from 2-isopropyl-phenol and
3-[3-(2-bromo-ethoxy)-phenyl]-2-methoxy-propionic acid methyl ester
(Example 351, Step 1) via the same procedure used for the
preparation of
(2S)-2-methoxy-3-[4-(3-phenoxy-propoxy)-phenyl]-propionic acid
(Example 285, Step 1). The enatiomers were separated by chiral
HPLC. MS (ES) for C.sub.2H.sub.26O.sub.5 [M-H].sup.-:357.2.
EXAMPLE 352
[2383]
2-methoxy-3-{3-[2-(3-methoxy-phenoxy)-ethoxy]-phenyl}-propionic
acid (isomer 1) 646
[2384] The title compound was prepared from 3-methoxy-phenol and
3-[3-(2-bromo-ethoxy)-phenyl]-2-methoxy-propionic acid methyl ester
(Example 351, Step 1) via the same procedure used for the
preparation of
(2S)-2-methoxy-3-[4-(3-phenoxy-propoxy)-phenyl]-propionic acid
(Example 285, Step 1). The enatiomers were separated by chiral
HPLC. MS (ES) for C.sub.19H.sub.22O.sub.6 [M-H].sup.-: 345.1.
EXAMPLE 353
[2385]
3-{3-[2-(3-fluoro-phenoxy)-ethoxy]-phenyl}-2-methoxy-propionic acid
(isomer 1) 647
[2386] The title compound was prepared from 3-fluoro-phenol and
3-[3-(2-bromo-ethoxy)-phenyl]-2-methoxy-propionic acid methyl ester
(Example 351, Step 1) via the same procedure used for the
preparation of
(2S)-2-methoxy-3-[4-(3-phenoxy-propoxy)-phenyl]-propionic acid
(Example 285, Step 1). The enatiomers were separated by chiral
HPLC. MS (ES) for C.sub.18H.sub.19O.sub.5 [M-H].sup.-: 333.1.
EXAMPLE 354
[2387]
2-methoxy-3-{3-[2-(5,6,7,8-tetrahydro-naphthalen-2-yloxy-ethoxy]-ph-
enyl}-propionic acid (isomer 1) 648
[2388] The title compound was prepared from
5,6,7,8-tetrahydro-naphthalen-- 2-ol and
3-[3-(2-bromo-ethoxy)-phenyl]-2-methoxy-propionic acid methyl ester
(Example 351, Step 1) via the same procedure used for the
preparation of
(2S)-2-methoxy-3-[4-(3-phenoxy-propoxy)-phenyl]-propionic acid
(Example 285, Step 1). The enatiomers were separated by chiral
HPLC. MS (ES) for C.sub.22H.sub.26O.sub.5 [M-H].sup.-: 369.2.
EXAMPLE 355
[2389]
2-methoxy-3-{3-[2-(3-methoxy-phenoxy)-ethoxy]-phenyl}-propionic
acid (isomer 2) 649
[2390] The title compound was prepared from 3-methoxy-phenol and
3-[3-(2-bromo-ethoxy)-phenyl]-2-methoxy-propionic acid methyl ester
(Example 351, Step 1) via the same procedure used for the
preparation of
(2S)-2-methoxy-3-[4-(3-phenoxy-propoxy)-phenyl]-propionic acid
(Example 285, Step 1). The enatiomers were separated by chiral
HPLC. MS (ES) for C.sub.19H.sub.22O.sub.6 [M-H].sup.31: 345.1.
EXAMPLE 356
[2391]
3-{3-[2-(3-fluoro-phenoxy)-ethoxy]-phenyl}-2-methoxy-propionic acid
(isomer 2) 650
[2392] The title compound was prepared from 3-fluoro-phenol and
3-[3-(2-bromo-ethoxy)-phenyl]-2-methoxy-propionic acid methyl ester
(Example 351, Step 1) via the same procedure used for the
preparation of (2S)-2-methoxy-3-[4-(3-phenoxy-propoxy)
phenyl]-propionic acid (Example-285, Step 1). The enatiomers were
separated by chiral HPLC. MS (ES) for C.sub.18H.sub.19FO.sub.5
[M-H].sup.-: 333.1.
EXAMPLE 357
[2393]
2-methoxy-3-{3-[2-(5,6,7,8-tetrahydro-naphthalen-2-yloxy)-ethoxy]-p-
henyl}-propionic acid (isomer 2) 651
[2394] The title compound was prepared from
5,6,7,8-tetrahydro-naphthalen-- 2-ol and
3-[3-(2-bromo-ethoxy)-phenyl]-2-methoxy-propionic acid methyl ester
(Example 351, Step 1) via the same procedure used for the
preparation of
(2S)-2-methoxy-3-[4-(3-phenoxy-propoxy)-phenyl]-propionic acid
(Example 285, Step 1). The enatiomers were separated by chiral
HPLC. MS (ES) for C.sub.22H.sub.26O.sub.5 [M-H].sup.-: 369.2.
EXAMPLE 358
[2395]
(2S)-2-methoxy-3-{4-[2-(4-trifluoromethyl-phenoxy)-ethoxy]-phenyl}--
propionic acid 652
[2396] The title compound was prepared from
(2S)-3-[4-(2-bromo-ethoxy)-phe- nyl]-2-methoxy-propionic acid ethyl
ester (Example 283, Step 2) and 4-trifluoromethyl-phenol via the
same procedure used for the preparation of
(2S)-2-methoxy-3-[4-(3-phenoxy-propoxy)-phenyl]-propionic acid
(Example 285, Step 1), to produce a white solid.
[2397] MS (ES) for C.sub.19H.sub.19F.sub.3O.sub.5 [M+Na].sup.+:
407.2.
EXAMPLE 359
[2398]
(2S)-2-methoxy-3-(4-{2-[4-(1-methyl-1-phenyl-ethyl)-phenoxy]-ethoxy-
}-phenyl)-propionic acid 653
[2399] The title compound was prepared from
(2S)-3-[4-(2-bromo-ethoxy)-phe- nyl]-2-methoxy-propionic acid ethyl
ester (Example 283, Step 2) and 4-(1-methyl-1-phenyl-ethyl)-phenol
via the same procedure used for the preparation of
(2S)-2-methoxy-3-[4-(3-phenoxy-propoxy)-phenyl]-propionic acid
(Example 285, Step 1), to produce a white solid.
[2400] MS (ES) for C.sub.7H.sub.30O.sub.5 [M+Na].sup.+: 457.2.
EXAMPLE 360
[2401]
(2S)-3-{4-[2-(4-benzyl-phenoxy)-ethoxy]-phenyl}-2-methoxy-propionic
acid 654
[2402] The title compound was prepared from
(2S)-3-[4-(2-bromo-ethoxy)-phe- nyl]-2-methoxy-propionic acid ethyl
ester (Example 283, Step 2) and 4-benzyl-phenol via the same
procedure used for the preparation of
(2S)-2-methoxy-3-[4-(3-phenoxy-propoxy)-phenyl]-propionic acid
(Example 285, Step 1), to produce a white solid. MS (ES) for
C.sub.25H.sub.26O.sub.5 [M+Na].sup.+: 429.3.
EXAMPLE 361
[2403]
(2S)-2-methoxy-3-{4-[2-(4-oxo-2-phenyl-4H-chromen-7-yloxy)-ethoxy]--
phenyl}-propionic acid 655
[2404] The title compound was prepared from
(2S)-3-[4-(2-bromo-ethoxy)-phe- nyl]-2-methoxy-propionic acid ethyl
ester (Example 283, Step 2) and 7-hydroxy-2-phenyl-chromen-4-one
via the same procedure used for the preparation of
(2S)-2-methoxy-3-[4-(3-phenoxy-propoxy)-phenyl]-propionic acid
(Example 285, Step 1), to produce a yellow solid.
[2405] MS (ES) for C.sub.27H.sub.24O.sub.7 [M+H].sup.+: 461.3.
EXAMPLE 362
[2406]
(2S)-3-{4-[2-(4-cyclopentyl-phenoxy)-ethoxy]-phenyl}-2-methoxy-prop-
ionic acid 656
[2407] The title compound was prepared from
(2S)-3-[4-(2-bromo-ethoxy)-phe- nyl]-2-methoxy-propionic acid ethyl
ester (Example 283, Step 2) and 1-cyclopentyl-4-methoxy-benzene via
the same procedure used for the preparation of
(2S)-2-methoxy-3-[4-(3-phenoxy-propoxy)-phenyl]-propionic acid
(Example 285, Step 1), to produce a white solid.
[2408] MS (ES) for C.sub.23H.sub.28O.sub.5 [M+Na].sup.+: 407.3.
EXAMPLE 363
[2409]
(2S)-3-{4-[2-(9H-fluoren-2-yloxy)-ethoxy]-phenyl}-2-methoxy-propion-
ic acid 657
[2410] The title compound was prepared from
(2S)-3-[4-(2-bromo-ethoxy)-phe- nyl]-2-methoxy-propionic acid ethyl
ester (Example 283, Step 2) and 9H-fluoren-2-ol via the same
procedure used for the preparation of
(2S)-2-methoxy-3-[(3-phenoxy-propoxy)-phenyl]-propionic acid
(Example 285, Step 1), to produce a white solid. MS (ES) for
C.sub.25H.sub.24O.sub.5 [M+Na].sup.+: 427.3.
EXAMPLE 364
[2411]
(2S)-3-[4-(2-butyl-phenoxy)-ethoxy-phenyl]-2-methoxy-propionic acid
658
[2412] Ile title compound was prepared from
(2S)-3-[4-(2-bromo-ethoxy)-phe- nyl]-2-methoxy-propionic acid ethyl
ester (Example 283, Step 2) and 4-butyl-phenol via the same
procedure used for the preparation of
(2S)-2-methoxy-3-[4-(3-phenoxy-propoxy)-phenyl]-propionic acid
(Example 285, Step 1), to produce a white solid. MS(ES) for
C.sub.22H.sub.28O.sub.5 [M+Na].sup.+: 395.3.
EXAMPLE 365
[2413]
(2S)-3-{4-[2-(2'-fluoro-biphenyl-4-yloxy)-ethoxy]-phenyl}-2-methoxy-
-propionic acid 659
[2414] The title compound was prepared from
(2S)-3-[4-(2-bromo-ethoxy)-phe- nyl]-2-methoxy-propionic acid ethyl
ester (Example 283, Step 2) and 2'-fluoro-biphenyl-4-ol via the
same procedure used for the preparation of
(2S)-2-methoxy-3-[4-(3-phenoxy-propoxy)-phenyl]-propionic acid
(Example 285, Step 1), to produce a white solid.
[2415] MS (ES) for C.sub.24H.sub.23FO.sub.5 [M+Na].sup.+:
433.3.
EXAMPLE 366
[2416]
(2S)-3-(4-{2-[4-(2,2-dimethyl-propionyl)-phenoxy]-ethoxy}-phenyl)-2-
-methoxy-propionic acid 660
[2417] The title compound was prepared from
(2S)-3-[4-(2-bromo-ethoxy)-phe- nyl]-2-methoxy-propionic acid ethyl
ester (Example 283, Step 2) and
1-(4-hydroxy-phenyl)-2,2-dimethyl-propan-1-one-1 via the same
procedure used for the preparation of
(2S)-2-methoxy-3-[4-(3-phenoxy-propoxy)-pheny- l]-propionic acid
(Example 285, Step 1), to produce a colorless oil. MS (ES) for
C.sub.23H.sub.28O.sub.6 [M+H].sup.+: 401.4.
EXAMPLE 367
[2418]
3-(4-{2-[4-(2,2-dimethyl-propionylamino)-phenoxy]-ethoxy}-phenyl)-2-
-methoxy-propionic acid 661
[2419] The title compound was prepared from
(2S)-3-[4-(2-bromo-ethoxy)phen- yl]-2-methoxy-propionic acid ethyl
ester (Example 283, Step 2) and
N-(4-hydroxy-phenyl)-2,2-dimethyl-propionamide via the same
procedure used for the preparation of
(2S)-2-methoxy-3-[4-(3-phenoxy-propoxy)-pheny- l]-propionic acid
(Example 285, Step 1), to produce a white solid. MS (ES) for
C.sub.23H.sub.29NO.sub.6 [M+H].sup.+: 416.4.
EXAMPLE 368
[2420]
(2S)-3-(4-{2-[4-(cyclopentanecarbonyl-amino)-phenoxy]-ethoxy}-pheny-
l)-2-methoxy-propionic acid 662
[2421] The title compound was prepared from
(2S)-3-[4-(2-bromo-ethoxy)-phe- nyl]-2-methoxy-propionic acid ethyl
ester (Example 283, Step 2) and cyclopentanecarboxylic acid
(4-hydroxy-phenyl)-amide via the same procedure used for the
preparation of (2S)-2-methoxy-3-[4-(3-phenoxy-prop-
oxy)-phenyl]-propionic acid (Example 285, Step 1), to produce a
white solid. MS (ES) for C.sub.24H.sub.29NO.sub.6 [M+H].sup.+:
428.3.
EXAMPLE 369
[2422]
(2S)-3-[4-(2-{4-[(furan-2-carbonyl)-amino]-phenoxy}-ethoxy)-phenyl]-
-2-methoxy-propionic acid 663
[2423] The title compound was prepared from
(2S)-3-[4-(2-bromo-ethoxy)-phe- nyl]-2-methoxy-propionic acid ethyl
ester (Example 283, Step 2) and furan-2-carboxylic acid
(4-hydroxy-phenyl)-amide via the same procedure used for the
preparation of
[2424] (2S)-2-methoxy-3-[4-(3-phenoxy-propoxy)-phenyl]-propionic
acid (Example 285, Step 1) to produce a white solid. MS (ES) for
C.sub.23H.sub.20O.sub.7 [M+H].sup.+: 426.3.
EXAMPLE 370
[2425]
(2S)-2-methoxy-3-[4-(2-{4-[(pyridine-3-carbonyl)-amino]-phenoxy}-et-
hoxy)-phenyl]-propionic acid 664
[2426] The title compound was prepared from
(2S)-3-[4-(2-bromo-ethoxy)-phe- nyl]-2-methoxy-propionic acid ethyl
ester (Example 283, Step 2) and N-(4-hydroxy-phenyl)-nicotinamide
via the same procedure used for the preparation of
(2S)-2-methoxy-3-[4-(3-phenoxy-propoxy)-phenyl]-propionic acid
(Example 285, Step 1), to produce a white solid. MS (ES) for
C.sub.24H.sub.24NO.sub.6 [M+H]+: 437.3.
EXAMPLE 371
[2427]
(2S)-2-methoxy-3-{4-[2-(2-pyrrolidin-1-yl-phenoxy)-ethoxy]-phenyl}--
propionic acid 665
[2428] The title compound was prepared from
(2S)-3-[4-(2-bromo-ethoxy)-phe- nyl]-2-methoxy-propionic acid ethyl
ester (Example 283, Step 2) and 2-pyrrolidin-1-yl-phenol via the
same procedure used for the preparation of
(2S)-2-methoxy-3-[4-(3-phenoxy-propoxy)-phenyl]-propionic acid
(Example 285, Step 1), to produce a yellow oil.
[2429] MS (ES) for C.sub.22H.sub.27NO.sub.5 [M+H].sup.+: 386.3.
EXAMPLE 372
[2430]
(2S)-2-methoxy-3-{4-[2-(pyridin-2-yloxy)-ethoxy]-phenyl}-propionic
acid 666
[2431] The title compound was prepared from
(2S)-3-[4-(2-bromo-ethoxy)-phe- nyl]-2-methoxy-propionic acid ethyl
ester (Example 283, Step 2) and pyridin-2-ol via the same procedure
used for the preparation of
(2S)-2-Methoxy-3-[4-(3-phenoxy-propoxy)-phenyl]-propionic acid
(Example 285, Step 1); to produce a colorless oil. MS (ES) for
C.sub.17H.sub.19NO.sub.5 [M+H].sup.+: 318.3.
EXAMPLE 373
[2432]
(2S)-2-methoxy-3-{4-[2-(2-morpholin-4-yl-phenoxy)-ethoxy]-phenyl}-p-
ropionic acid. 667
[2433] The title compound was prepared from
(2S)-3-[4-(2-bromo-ethoxy)-phe- nyl]-2-methoxy-propionic acid ethyl
ester (Example 283, Step 2) and 2-morpholin-4-yl-phenol via the
same procedure used for the preparation of
(2S)-2-methoxy-3-[4-(3-phenoxy-propoxy)-phenyl]-propionic acid
(Example 285, Step 1), to produce a colorless oil.
[2434] MS (ES) for CH.sub.27NO.sub.6 [M+H].sup.+: 402.3.
EXAMPLE 374
[2435]
(2S)-3-{4-[2-(4'-tert-butyl-biphenyl-4-yloxy)-ethoxy]-phenyl}-1-met-
hoxy-propionic acid 668
[2436] The title compound was prepared from
(2S)-3-[4-(2-bromo-ethoxy)-phe- nyl]-2-methoxy-propionic acid ethyl
ester Example 283, Step 2) and 4'-tert-butyl-biphenyl-4-ol via the
same procedure used for the preparation of
(2S)-2-methoxy-3-[4-(3-phenoxy-propoxy)-phenyl]-propionic acid
(Example 285, Step 1), to produce a white solid.
[2437] MS (ES) for C.sub.28H.sub.32O.sub.5 [M-H].sup.-: 447.2.
EXAMPLE 375
[2438]
(2S)-2-ethoxy-3-{4-[2-(4-phenoxy-phenoxy)-ethoxy]-phenyl}-propionic
acid 669
[2439] Step 1: 3-(4-benzyloxy-phenyl)-2-ethoxy-3-hydroxy-propionic
acid ethyl ester 670
[2440] The title compound was preoared from
4-benzyloxybenzaldehyde, lithium diisopropylamide and ethyl
2-ethoxyacetate via the same procedure used for the preparation of
3-(3-benzyloxy-phenyl)-3-hydroxy-2-methoxy propionic acid methyl
ester (Example 291, Step 1). MS (ES) for C.sub.20H.sub.24O.sub.5
[M+H.sub.2O-H].sup.+: 327, [M+Na].sup.+: 367.4.
[2441] Step 2: 3-(4-benzyloxy-phenyl)-2-ethoxy-acrylic acid ethyl
ester 671
[2442] The title compound was prepared from
3-(4-benzyloxy-phenyl)-2-ethox- y-3-hydroxy-propionic acid ethyl
ester (Example 375, Step 1) via the same procedure used for the
preparation of 3-(4-benzyloxy-phenyl)-2-ethoxy-acr- ylic acid
methyl ester. MS (ES) for C.sub.20H.sub.22O.sub.4 [M+H].sup.+:
327.2.
[2443] Step 3: 3-(4-benzyloxy-phenyl)-2-ethoxy-propionic acid
methyl ester 672
[2444] The title compound was prepared from
3-(4-benzyloxy-phenyl)-2-ethox- y-acrylic acid ethyl ester (Example
375, Step 2) (3.3 gr, 10.12 mmol) via the same procedure used for
the preparation of 3-(3-benzyloxy-phenyl)-2-m- ethoxy-propionic
acid methyl ester (Example 291, Step 3) to produce an oil that was
purified by chromatography (silica gel, hexanes/ethyl acetate 6:1)
to produce two compounds: 3-(4-benzyloxy-phenyl)-propionic acid
methyl ester (1.5 gr, Rf aprox. 0.65) and the desired compound (1.5
gr, Rf aprox. 0.2).
[2445] MS (ES) for C.sub.19H.sub.22O.sub.4 [M+NH.sub.4].sup.+:
332.3.
[2446] Step 4: 2-ethoxy-3-(4-hydroxy-phenyl)-propionic acid methyl
ester 673
[2447] The title compound was prepared from
3-(4-benzyloxy-phenyl)-2-ethox- y-propionic acid methyl ester
(example 375, Step 3) via the same procedure used for the
preparation of 3-(3-hydroxy-phenyl)-2-methoxy-propionic acid methyl
ester (Example 291, Step 4) to produce a yellow oil. MS (ES) for
C.sub.12H.sub.16O.sub.4 [M+H].sup.+: 225.2, [M+NH.sub.4].sup.+:
242.2, [M+Na].sup.+: 247.2.
[2448] Step 5: 4-(2-bromo-ethoxy)-phenoxyphenyl 674
[2449] The title compound was prepared from 4-phenoxy-phenol via
the same procedure used for the preparation of
(2S)-3-[4-(2-bromo-ethoxy)-phenyl]-- 2-methoxy-propionic acid ethyl
ester (Example 283, Step 2) to produce a white solid. MS (ES) for
C.sub.14H.sub.13BrO.sub.2 [M-H].sup.-: 291.0.
[2450] Step 6:
(2S)-2-ethoxy-3-{4-[2-(4-phenoxy-phenoxy)-ethoxy]-phenyl}-p-
ropionic acid 675
[2451] The title compound was prepared from
2-ethoxy-3-(4-hydroxy-phenyl)-- propionic acid methyl ester Example
375, Step 4) and 4-(2-bromo-ethoxy)-phenoxyphenyl (Example 375,
Step 5) via the same procedure used for the preparation of
(2S)-3-{4-[2-(biphenyl-4-yloxy)-eth-
oxy]-phenyl}-2-methoxy-propionic acid (Example 283, Step 3). The
crude material was submitted to chiral HPLC separation to afford
the single enantiomer isomer 2. MS (ES) for C.sub.25H.sub.26O.sub.6
[M-H].sup.-: 421.4.
EXAMPLE 376
[2452]
(2R)-2-ethoxy-3-{4-[2-(4-phenoxy-phenoxy)-ethoxy]-phenyl}-propionic
acid 676
[2453] The title compound was prepared from
2-ethoxy-3-(4-hydroxy-phenyl)-- propionic acid methyl ester
(Example 375, Step 4) and 4-(2-bromo-ethoxy)-phenoxyphenyl (Example
375, Step 5) via the same procedure used for the preparation of
(2S)-3-{4-[2-(biphenyl-1 yloxy)-ethoxy]-phenyl}-2-methoxy-propionic
acid (Example 283, Step 3). The crude material was submitted to
chiral HPLC separation to afford the single enantiomer isomer 1. MS
(ES) for C.sub.25H.sub.26O.sub.6 [M-H].sup.-: 421.4.
EXAMPLE 377
[2454]
(2S)-3-{4-[2-(biphenyl-4-yloxy)-ethoxy]-phenyl}-2-propoxy-propionic
acid 677
[2455] Step 1: 4-(2-bromo-ethoxy)biphenyl 678
[2456] The title compound was prepared from biphenyl-4-ol via the
same procedure used for the preparation of
(2S)-3-[4-(2-bromo-ethoxy)-phenyl]-- 2-methoxy-propionic acid ethyl
ester (Example 283, Step 2) to produce a white solid. MS (ES) for
C.sub.14H.sub.13BrO [M-H].sup.-: 279.1.
[2457] Step 2: (2S)-3-(4-benzyl-phenyl)-2-hydroxy-propionic acid
ethyl ester 679
[2458] The title compound was prepared from
(2S)-3-(4-benzyloxy-phenyl)-2-- hydroxy-propionic acid via the same
procedure used for the preparation of
(2S)-3-(4-hydroxy-phenyl)-2-methoxy-propionic acid ethyl ester
(Example 283, Step 1) to afford the product as a yellow oil.
.sup.1H-NMR (CDCl.sub.3, 200.15 MHz): 7.35-7.55 (m, 5H), 7.20 (d,
2H, J=8.3), 6.79 (d, 2H, J=8.3), 4.99 (s, 2H), 4.41 (dd, 1H, J=6.5,
4.4), 4.19 (c, 2H, J=6.9), 2.92 (2dd, 2H, J=16.1, 4.4), 1.23 (t,
3H, J=6.9).
[2459] Step 3: (2S)-3-(4-benzyloxy-phenyl)-2-propoxy-propionic acid
ethyl ester 680
[2460] Propyl iodide (41.6 mmol) was added at room temperature to a
solution of (2S)-34 benzyloxy-phenyl)-2-hydroxy-propionic acid
ethyl ester (Example 377, Step 2) (8.3 mmol) and silver oxide
(12.45 mmol) in 40 mL of DMF. The mixture was heated at 50.degree.
C. for 24 hours. After that the mixture was cooled to room
temperature, 300 ml of ethyl acetate and 200 ml of water were
added. The aqueous layer was separated and the organic layer were
washed with brine (3.times.100 ml), and then dried over
(MgSO.sub.4), filtered and concentrated under vacuum. The crude was
purified by chromatography (silica gel, hexanes/ethyl acetate 6:1)
to produce a yellow oil. .sup.1H-NMR (CDCl.sub.3, 200.15 MHz):
7.42-7.31 (m, 5H), 7.17 (d, 2H, J=8.6 Hz), 6.90 (d, 2H, J=8.6 Hz),
5.05 (s, 2H), 4.17 (q, 2H, J=7.0 Hz), 3.97 (dd, 1H, J=7.0, 6.2 Hz),
3.53 (dt, 1H, J=8.9, 6.4 Hz), 3.23 (dt, 1H, J=9.1, 6.7 Hz), 2.97
(d, 2H, J=6.7 Hz), 1.66-1.48 (m, 2H), 1.23 (t, 3H, J=7.3 Hz), 0.86
(t, 3H, J=7.5 Hz).
[2461] Step 4: (2S)-3-(4-hydroxy-phenyl)-2-propoxy-propionic acid
ethyl ester 681
[2462] The title compound was prepared from (2S)-3-(4-be
yloxy-phenyl)-2-propoxy-propionic acid ethyl ester (Example 377,
Step 3) via the same procedure used for the preparation of
3-(3-hydroxy-phenyl)-2-methoxy-propionic acid methyl ester (Example
291, Step 4) to produce a yellow oil. MS (ES) for
C.sub.14H.sub.20O.sub.4 [M+H].sup.+: 253.1.
[2463] Step 5:
(2S)-3-{4-[2-(biphenyl-4-yloxy)-ethoxy]-phenyl}-2-propoxy-p-
ropionic acid 682
[2464] The title compound was prepared from
4-(2-bromo-ethoxy)-biphenyl (Example 377, Step 1) and
(2S)-3-(4-hydroxy-phenyl)-2-propoxy-propionic acid ethyl ester
(Example 377, Step 4) via the same procedure used for the
preparation of
(2S)-3-{4-[2-(biphenyl-4-yloxy)-ethoxy]-phenyl}-2-meth-
oxy-propionic acid (Example 283, Step 3) to produce a white solid.
MS (ES) for C.sub.26H.sub.28O.sub.5 [M+H].sup.+: 421.0,
[M+NH.sub.4].sup.+: 438.0, [M+Na].sup.+: 443.0, [M-H].sup.-:
3239.2.
EXAMPLE 378
[2465]
3-{3-[3-(biphenyl-4-yloxy)-propoxy]-phenyl}-2-ethoxy-propionic acid
(isomer 1) 683
[2466] Step 1: 3-(3-benzyloxy-phenyl)-2-ethoxy-3-hydroxy-propionic
acid ethyl ester 684
[2467] The title compound was prepared from
3-benzyloxy-benzaldehyde and ethyl ethoxyacetate via the same
procedure used for the preparation of
3-(3-benzyloxy-phenyl)-3-hydroxy-2-methoxy-propionic acid methyl
ester (Example 291, Step 1) to afford the title compound as a
colorless oil.
[2468] Step 2: 3-(3-benzyloxy-phenyl)-2-ethoxy-acrylic acid ethyl
ester 685
[2469] The title compound was prepared from
3-(3-benzyloxy-phenyl)-2-ethox- y-3-hydroxy-propionic acid ethyl
ester (Example 378, Step 1) via the same procedure used for the
preparation of 3-(3-benzyloxy-phenyl)-2-methoxy-ac- rylic acid
methyl ester (Example 291, Step 2) to afford the title compound as
a colorless oil.
[2470] Step 3: 3-(3-benzyloxy-phenyl)-2-ethoxy-propionic acid
methyl ester 686
[2471] The title compound was prepared from
3-(3-benzyloxy-phenyl)-2-ethox- y-acrylic acid ethyl ester Example
378, Step 2) via the same procedure used for the preparation of
3-(3-benzyloxy-phenyl)-2-methoxy-propionic acid methyl ester
(Example 291, Step 3) to afford the title compound as a colorless
oil.
[2472] Step 4: 2-ethoxy-3-(3-hydroxy-phenyl)-propionic acid methyl
ester 687
[2473] The title compound was prepared from
3-(3-benzyloxy-phenyl)-2-ethox- y-propionic acid methyl ester
(Example 378, Step 3) via the same procedure used for the
preparation of 3-(3-hydroxy-phenyl)-2-methoxy-propionic acid methyl
ester (Example 291, Step 4) to afford the title compound as a
yellow oil. MS(ES) for C.sub.12H.sub.16O.sub.4 [M+H].sup.+:
225.1.
[2474] Step 5:
(3-{3-[3-(biphenyl-4-yloxy)-propoxy]-phenyl}-2-ethoxy-propi- onic
acid (isomer 1) 688
[2475] The title compound was prepared from
3-(biphenyl-4-yloxy)-propan-1-- ol (Example 291, Step 6) and
2-ethoxy-3-(3-hydroxy-phenyl)-propionic acid methyl ester (Example
378, Step 4) via the same procedure used for the preparation of
(2S)-3-{4-[2-(biphenyl-4-yloxy)-ethoxy]-phenyl}-2-methoxy--
propionic acid (Example 283, Step 3) to produce a white solid. The
crude material was submitted to chiral HPLC separation to afford
the single enantiomer isomer 1. (ES) for C.sub.26H.sub.28O.sub.5
[M+NH.sub.4].sup.+: 438.0, [M+Na].sup.+: 443.0.
EXAMPLE 379
[2476] 689
[2477] The title compound was prepared from
3-(biphenyl-4-yloxy)-propan-1-- ol (Example 291, Step 6) and
2-ethoxy-3-(3-hydroxy-phenyl)-propionic acid methyl ester (Example
378, Step 4) via the same procedure used for the preparation of
(2S)-3-{4-[2-(biphenyl-4-yloxy)-ethoxy]-phenyl}-2-methoxy--
propionic acid (Example 283, Step 3) to produce a white solid. The
crude material was submitted to chiral HPLC separation to afford
the single enantiomer isomer 2. MS (ES) for C.sub.26H.sub.28O.sub.5
[M+NH.sub.4].sup.+: 438.0, [M+Na].sup.+: 443.0.
EXAMPLE 380
[2478] Binding Assay:
[2479] DNA-dependent binding was carried out using Scintillation
Proximity Assay (SPA) technology. PPAR.gamma. as well as its
heterodimeric partner RXR.alpha. were prepared using a baculovirus
expression system. A biotinylated complementary oligonucleotide
duplex representing the human consensus PPR response element was
used for binding receptor dimer to Yttrium silicate
streptavidin-coated SPA beads. The 5'-3' strand had the sequence:
.sup.5'TAATGTAGGTAATAGTFCAATAGGTCAAAGG.sup.3' (SEQ ID NO: 1);
biotin was bound to the first A at the 3' end of the complementary
3'-5' strand. The PPAR.gamma. labeled ligand was
.sup.3H-(s)-3-{4-[3-(biphenyl--
4-yloxy)-propoxy]-phenyl}-2-methoxy-propionic acid with specific
activiy of 24 Ci/mmol. The binding assay was carried out on 96 well
dishes. Per well, 100 ng of oligonucleotide was preincubated with 3
.mu.g SPA beads in a binding buffer containing 10 mM HEPES pH 7.8,
80 mM KCl, 0.5 mM MgCl.sub.2, 1 mM DTT, 0.5% CHAPS and 16.6 .mu.g
bovine serum albumin for 30 minutes at room temperature. The
mixture was then spun at 2000 rpm for 3 minutes to pellet the
beads-oligo mix. The supernatant was removed, and the beads-oligo
pellet was resuspended in the same binding buffer as above but also
containing 14% glycerol, 5 .mu.g sheared salmon sperm DNA and 2.5
.mu.g of each receptor, PPAR.gamma. and RXR.alpha.. A saturation
binding assay was carried out using increasing amounts of
.sup.3H-(s)-3-{4-[3-(biphenyl-4-yloxy)-propoxy]-phenyl}-2-methoxy-propion-
ic acid in the reaction to obtain 0.39 nM to 402 nM of .sup.3
H-(s)-3-{4-[3-(biphenyl-4-yloxy)-propoxy]-phenyl}-2-methoxy-propionic
acid. Non-specific binding was measured in the presence of 10 M of
unlabeled
(s)-3-{4-[3-(biphenyl-4-yloxy)-propoxy]-phenyl}-2-methoxy-propi-
onic acid. A K.sub.d value was calculated from the saturation
binding experiments after plotting specific binding versus
concentration of labeled ligand. Competition binding reactions were
carried in the presence of 30,000 cpm of
.sup.3H-(s)-3-{4-[3-(biphenyl-4-yloxy)-propoxy]-
-phenyl}-2-methoxy-propionic acid and 5 nM to 10 .mu.M of competing
compounds. The IC.sub.50 (nM) values for competing compounds were
calculated after deduction of non-specific binding (measured in the
presence of 10 .mu.M unlabeled
.sup.3H-(s)-3-{4-[3-(biphenyl-4-yloxy)-pro-
poxy]-phenyl}2-methoxy-propionic acid), and the data normalized to
total binding (if the absence of any unlabeled compound). The
.sup.3H-(s)-3-{4-[3-(biphenyl-4-yloxy)-propoxy]-phenyl}-2-methoxy
propionic acid was effective in determining the binding affinity of
PPAR subtypes in the range of 5 nM to 10000 nM. For example, PPAR
compounds with
[2480] IC.sub.50 values less than 500 nM were identified as ligands
for PPAR gamma
[2481] Preparation of
3H-(s)-3-{4-[3-(biphenyl-4-yloxy-propoxy]-phenyl}-2--
methoxy-propionic acid 690
[2482] In a reaction vessel
(s)-3-{4-[3-(4'-bromo-biphenyl-4-yloxy)-propox-
y]-phenyl}-2-methoxy-propionic acid (6.1 mg) was combined with 10%
Pd/CaCO.sub.3 (18.6 mg), DMF (0.5 ml) and methanol (0.5 ml). The
mixture was stirred under 10 Ci of tritium gas for about 4.5 hours.
The catalyst was removed by filtration, and the labile activity was
removed by repeated rotary evaporations with methanol. The final
residue was dissolved in ethanol. The crude product was purified by
reverse phase HPLC eluting with a water/acetonitrile/TFA gradient
system. The major UV and radioactive peak was collected and rotary
evaporated to dryness. The resulting residue was dissolved in
ethanol (yield: 102 mCi)
EXAMPLE 381
[2483] Binding and Cotransfection Studies
[2484] The in vitro potency of compounds in modulating PPAR.alpha.
and PPAR.gamma. receptors were determined by the procedures
detailed below. DNA-dependent binding (ABCD binding) was carried
out using Scintillation Proximity Assay (SPA) technology with PPAR
receptors. Tritium-labeled PPAR.alpha. and PPAR.gamma. agonists
were used as radioligands for generating displacement curves and
IC.sub.50 values with compounds of the present invention.
Cotransfection assays were carried out in CV-1 cells. The reporter
plasmid contained an acylCoA oxidase (AOX) PPRE and TK promoter
upstream of the luciferase reporter cDNA. Appropriate PPARs and
RXR.alpha. were constitutively expressed using plasmids containing
the CMV promoter. Since for PPAR.alpha. and PPAR.beta./.delta.,
interference by endogenous PPAR.gamma. in CV-1 cells is an issue,
in order to eliminate such interference, a GAL4 chimeric system was
used in which the DNA binding domain of the transfected PPAR is
replaced by that of GAL4, and the GAL4 response element was
utilized in place of the AOX PPRE. Cotransfection efficacy was
determined relative to PPAR-isotope specific reference compounds.
Efficacies were determined by computer fit to a
concentration-response curve, or in some cases at a single high
concentration of agonist (10 .mu.M). Typical range for
concentration determination IC.sub.50 is in the range of 1 nM to 10
.mu.M. For binding or cotransfection studies with receptors other
than PPARs, similar assays were carried out using appropriate
ligands, receptors, reporter constructs for that particular
receptor.
[2485] These studies were carried out to evaluate the ability of
compounds of the present invention to bind to and/or activate
various nuclear transcription factors, particularly huPPAR.alpha.
("hu" indicates "human") and huPPAR.gamma.. These studies provided
in-vitro data concerning efficacy and selectivity of compounds of
the present invention. Furthermore, binding and cotransfection data
for compounds of the present invention were compared with
corresponding data for marketed compounds that act on either
huPPAR.alpha. or huPPAR.gamma.. Binding and cotransfection data for
representative compounds of the present invention were compared
with corresponding data for reference compounds to determine the
binding.
[2486] The concentration of test compound required to effect 50%
maximal activation of PPAR.alpha. (IC.sub.50.alpha.) and
PPAR.gamma. (IC.sub.50.gamma.) was determined. Many of the
compounds of the present invention are selective agonists for
PPAR.gamma. or are co-agonists of PPAR.alpha./PPAR.gamma..
[2487] Evaluation of Triglyceride and Cholesterol Levels in HuapoAI
Transgenic Mice
[2488] Five to six week old male mice, transgenic for human apoAI
[C57Bl/6-tgn(apoa1)1rub, Jackson Laboratory, Bar Harbor, Me.] were
housed five per cage (10".times.20".times.8" with aspen chip
bedding) with food (Purina 5001) and water available at all times.
After an acclimation period of 2 weeks, animals were individually
identified by ear notches, weighed and assigned to groups based on
body weight. Beginning the following morning, mice were dosed daily
by oral gavage for 7 days using a 20 gauge, 11/2" curved disposable
feeding needle. Treatments were test compounds (30 mg/kg), a
positive control (fenofibrate, 100 mg/kg) or vehicle [1%
carboxymethylcellulose (w/v)/0.25% Tween80 (w/A); 0.2 ml/mouse].
Prior to termination on day 7, mice were weighed and dosed. Three
hours after dosing, animals were anesthetized by inhalation of
isoflurane (2-4%) and blood obtained via cardiac puncture (0.7-1.0
ml). Whole blood was transferred to serum separator tubes
(Vacutainer SST), chilled on ice and permitted to clot. Serum, was
obtained after centrifugation at 4.degree. C. and frozen until
analysis for triglycerides, total cholesterol, compound levels and
serum lipoprotein profiled by fast protein liquid, chromatography
(FPLC) coupled to an inline detection system. After sacrifice by
cervical dislocation, the liver, heart and epididymal fat pads were
excised and weighed.
[2489] The animals dosed with vehicle had average triglycerides
values of about 60 to 80 mg/dl, which were reduced by the positive
control fenofibrate (33-58 mg/dl with a mean reduction of 37%). The
animals dosed with vehicle have average total serum cholesterol
values of about 140 to 180 mg/dl, which were increased by
fenofibrate (about 190 to 280 mg/dl with a mean elevation of 41%).
When subject to FPLC analysis, pooled sera from vehicle-treated hu
apoAI transgenic mice had a high-density lipoprotein cholesterol
(HDLc) peak area which ranged from 47v-sec to 62v-sec. Fenofibrate
increased the amount of HDLc (68-96v-sec with a mean percent
increase of 48%). Test compounds were evaluated in terms of percent
increase in the area under the curve. Representative compounds of
the present invention were tested using the above method or
substantially similar methods.
[2490] Evaluation of Glucose Levels in db/db Mice
[2491] Five week old male diabetic (db/db) mice
[C57BIKs/j-m+/+Lepr(db), Jackson Laboratory, Bar Harbor, Me.] or
lean littermates (db+) were housed 6 per cage
(10".times.20".times.8" with aspen chip bedding) with food (Purina
5015) and water available at all times. After an acclimation period
of 2 weeks, animals were individually identified by ear notches,
weighed and bled via the tail vein for determination of initial
glucose levels. Blood was collected (100 .mu.l) from unfasted
animals by wrapping each mouse in a towel, cutting the tip of the
tail with a scalpel, and milking blood from the tail into a
heparinized capillary tube balanced on the edge of the bench.
Sample was discharged into a heparinized microtainer with gel
separator (VWR) and retained on ice. Plasma was obtained after
centrifugation at 4.degree. C. and glucose was measured
immediately. Remaining plasma was frozen until the completion of
the experiment, and glucose and triglycerides were assayed in all
samples. Animals were grouped based on initial glucose levels and
body weights. Beginning the following morning, mice were dosed
daily by oral gavage for 7 days using a 20 gauge, 11/2" curved
disposable feeding needle. Treatments were test compounds (30
mg/kg), a positive control agent (30 mg/kg) or vehicle [1%
carboxymethylcellulose (w/v)/0.25% Tween80 (w/v); 0.3 ml/mouse]. On
day 7, mice were weighed and bled (tail vein) for about 3 hours
after dosing. Twenty-four hours after the 7.sup.th dose (i.e., day
8), animals were bled again (tail vein). Samples obtained from
conscious animals on days 0, 7 and 8 were assayed for glucose.
After 24 hour bleed, animals were weighed and dosed for the final
time. Three hours after dosing on day 8, animals were anesthetized
by inhalation of isoflurane, and blood obtained was via cardiac
puncture (0.5-0.7 ml). Whole blood was transferred to serum
separator tubes, chilled on ice and permitted to clot. Serum was
obtained after centrifugation at 4.degree. C. and frozen until
analysis for compound levels. After sacrifice by cervical
dislocation, the liver, heart and epididymal fat pads were excised
and weighed.
[2492] The animals dosed with vehicle-had average triglycerides
values of about 170 to 230 mg/dl, which were reduced by the
positive PPAR.gamma. control (about 70 to 120 mg/dl with a mean
reduction of 50%). Male db/db mice are hyperglycemic (average
glucose of about 680 to 730 mg/dl on the 7.sup.th day of
treatment), while lean animals have average glucose levels between
about 190 and 230 mg/dl. Treatment with the positive control agent
reduced glucose significantly (about 350 to 550 mg/dl with a mean
decrease towards normalization of 56%).
[2493] Glucose was measured colorimetrically by using commercially
purchased reagents (Sigma #315-500). According to the
manufacturers, the procedures were modified from published work
(McGowan et al. Clin Chem, 20:470-5 (1974) and Keston, A. Specific
colorimetric enzymatic analytical reagents for glucose. Abstract of
papers 129th Meeting ACS, 31C (1956).); and depend on the release
of a mole of hydrogen peroxide for each mole of analyte coupled
with a color reaction first described by Trinder (Trinder, P. Ann
Clin Biochem, 6:24 (1969)). The absorbance of the dye produced was
linearly related to the analyte in the sample. The assays was
further modified for use in a 96 well format. Standards (Sigma
#339-11, Sigma #16-11, and Sigma #CC0534 for glucose, triglycerides
and total cholesterol, respectively), quality control plasma (Sigma
# A2034), and samples-(2 or 5 .mu.well) were measured in duplicate
using 200 .mu.l of reagent. An additional aliquot of sample,
pipetted to a third well and diluted in 200 .mu.l water, provided
ai blank for each specimen. Plates were incubated at room
temperature (18, 15, and 10 minutes for glucose, triglycerides and
total cholesterol, respectively) on a plate shaker and absorbance
read at 500 nm (glucose and total cholesterol) or 540 in
(triglycerides) on a plate reader. Sample absorbance was compared
to a standard curve (100-800, 10-500, and 100-400 mg/dl for
glucose, triglycerides and total cholesterol, respectively). Values
for the quality control sample wee consistently within the expected
range and the coefficient of variation for samples is below 10%.
All samples from an experiment were assayed at the same time to
minimize inter-assay variability.
[2494] Serum lipoproteins were separated and cholesterol was
quantitated with an in-line detection system. Sample was applied to
a Superose.RTM. 6 HR 10/30 size exclusion column (Amersham
Pharmacia Biotech) and eluted with phosphate buffered saline-EDTA
at 0.5 ml/min. Cholesterol reagent (Roche Diagnostics Chol/HP
704036) at 0.16 ml/min was mixed with the column effluent through a
T-connection, and the mixture was passed through a 15 m.times.0.5
mm id knitted tubing reactor immersed in a 37.degree. C. water
bath. The colored product produced in the presence of cholesterol
was monitored in the flow stream at 505 nm, and the analog voltage
from the monitor was converted to a digital signal for collection
and analysis. The change in voltage corresponding to change in
cholesterol concentration was plotted against time, and the area
under the curve corresponding to the elution of VLDL; LDL and HDL
was calculated (Perkin Elmer Turbochrome software).
[2495] While this invention has been particularly shown and
described with references to preferred embodiments thereof, it will
be understood by those skilled in the art that various changes in
form and details maybe made therein without departing from the
scope of the invention encompassed by the appended claims.
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